Compounds and methods for treating candidiasis and aspergillus infections

ABSTRACT

The present disclosure provides compounds, or pharmaceutically acceptable salts thereof, for killing or inhibiting the growth of a  Candida  or  Aspergillus  species or preventing or treating a mammal having candidiasis (oral and/or disseminated) or an  Aspergillus  infection.

REFERENCE TO GOVERNMENT GRANTS

The present disclosure was supported by funds from the U.S. Government(NIH/NIDCR Grant No. 2R44DE018371-02) and the Government may thereforehave certain rights in the disclosure.

FIELD

The present disclosure is directed, in part, to compounds, orpharmaceutically acceptable salts thereof, and pharmaceuticalcompositions comprising the same, and methods for treating a mammalhaving candidiasis, such as oral candidiasis and/or disseminatedcandidiasis, and/or an aspergillus infection.

BACKGROUND

Candidiasis encompasses fungal infections caused by a variety of speciesof the genus Candida, in particular mostly by Candida albicans, which isa yeast-like fungus. Candida spp. are normally present in the mouth,vagina, and intestines of healthy individuals; normal bacteria in theseareas keep the amount of Candida spp. in check. Infection of candidalfungi normally depends on a weakened immune status of an individual toinvade tissue that normally would be resistant to infection and theopportunity to gain access to the circulatory system. Candida infectionsthat develop in immunocompromised individuals can affect the entire body(e.g., disseminated or systemic candidiasis) and may become lifethreatening. The most common condition is topical candidiasis (fungusgrowing on the surface of the body). An example of this is a common formof “diaper rash” in infants. Topical candidiasis can affect the skin,the vagina, the mouth (e.g., oral candidiasis) and the esophagus, and inimmunocompromised individuals (e.g., HIV patients).

Candida infections are opportunistic and generally begin with increasedcolonization of the junction of mucous membranes and skin surfaces ofvulnerable parts of the body such as, for example, oral, nasal, vaginal,and anal orifices, and the lining of the respiratory tract. Under someabnormal conditions, including the reduction of normal bacteria in aparticular part of the body or skin defects such as wounds, ulcerations,and burns, the fungi can overgrow and cause infection of the outerlayers of the skin and mucous membranes. This may occur in the mouth(oral thrush), in the vagina or penis (genital candidiasis), betweenfolds and surfaces of skin (intertrigo), and in and around the nails(paronychia and onychomycosis).

In some instances, the fungus enters the bloodstream and causesdisseminated disease affecting internal body organs such as the kidneys,spleen, lungs, liver, eyes, meninges, brain, and heart valves. Thiscondition is called systemic or disseminated candidiasis; it can resultin a range of diseases such as superficial mucocutaneous disease,candidiasis of the liver and spleen (hepatosplenic candidiasis), andperitonitis. This is usually seen in patients who are seriously ill withother diseases who have been receiving potent antibiotics that treatbacterial infection.

Oral candidiasis (sometimes referred to as “thrush”) is an infection inwhich the fungus of the genus Candida (a yeast) accumulates on themucous membranes of the mouth. It is most often caused by Candidaalbicans, or less commonly by Candida glabrata or Candida tropicalis. Ifoccurring in the mouth of a baby, the candidiasis is commonly referredto as oral thrush, whereas if occurring in the mouth or throat of anadult, it may also be termed candidosis or moniliasis.

Oral infection by Candida species may not be immediately noticeable butcan develop suddenly and may persist for a long time. The infectionusually appears as thick white or cream-colored deposits on mucosalmembranes such as the tongue, inner cheeks, gums, tonsils, and palate.The infected mucosa may appear inflamed (red and possibly slightlyraised) and sometimes have a cottage cheese-like appearance. The lesionscan be painful and may become tender and often bleed if rubbed orscraped. Cracking at the corners of the mouth, a cottony-like sensationinside the mouth, and even temporary loss of taste can occur. In moresevere cases, the infection can spread down the esophagus and causedifficulty swallowing, which is sometimes referred to as esophagealcandidiasis. Thrush does not usually cause a fever unless the infectionhas spread beyond the esophagus to other body parts, such as the lungs(i.e., systemic candidiasis).

Although oral thrush can affect anyone, it is more likely to occur inbabies and in people who wear dentures, use inhaled corticosteroids, orhave compromised immune systems. Oral thrush and other Candidainfections can occur when the immune system is weakened by disease ordrugs such as prednisone, or when antibiotics disturb the naturalbalance of microorganisms in the body. Normally, the immune systemrepels harmful invading organisms, such as fungi, while maintaining abalance between “good” and “bad” microbes that normally inhabit thebody. When these protective mechanisms fail, however, an oral thrushinfection may take hold.

The following diseases or conditions may make one more susceptible tooral thrush infection:

1) HIV/AIDS. The human immunodeficiency virus (HIV) damages or destroyscells of the immune system, making one more susceptible to opportunisticinfections. Repeated bouts of oral thrush may be the first sign of anHIV infection.

2) Cancer. The immune system is likely to be weakened from the diseaseand from treatments, such as chemotherapy and radiation. Both thedisease and treatments can increase the risk of Candida infections suchas oral thrush.

3) Diabetes mellitus. In untreated or under-treated diabetes, the salivamay contain large amounts of sugar, which encourages the growth ofCandida.

4) Vaginal yeast infections. Vaginal yeast infections are caused by thesame fungus that causes oral thrash. Although a yeast infection is nottypically dangerous, a pregnant female can pass the fungus to the babyduring delivery.

Oral candidiasis can be treated with topical anti-fungal drugs, such asnystatin, miconazole, Gentian violet, or amphotericin B. Topical therapyis normally provided as an oral suspension which is washed around themouth and then swallowed by the patient. Patients who areimmunocompromised, either with HIV/AIDS or as a result of chemotherapy,may require systemic treatment with oral or intravenous administeredanti-fungals. Some anti-fungal medications, however, may cause liverdamage. For this reason, a physician will likely perform blood tests tomonitor liver function, especially if prolonged treatment is required orthere is a history of liver disease.

Some Aspergillus species cause serious disease in humans and animals.The most common pathogenic species include Aspergillus fumigatus andAspergillus flavus. Aspergillus flavus produces aflatoxin which is botha toxin and a carcinogen, and which can contaminate foods. The mostcommon causing allergic disease are Aspergillus fumigatus andAspergillus clavatus. Other species, Aspergillus spp., are importantagricultural pathogens.

SUMMARY

The present disclosure provides compounds of Formula I:

wherein: each X is, independently, O, S, or S(═O)₂; each R¹ is,independently, —CH₃, —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 to 4, and eachR⁴ is, independently, H, —C₁-C₃alkyl, or —(CH₂)_(p)—NH₂, where each pis, independently, 1 or 2; each R² is, independently, H, halo, —CF₃, or—C(CH₃)₃; each V² is H, and each V¹ is, independently, —N—C(═O)—R³,where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachV¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; and each R⁶ is H, —S—(CH₂)_(m)—NH₂,—S—(CH₂)_(m)—NH—C(═NH)NH₂, —O—(CH₂)_(m)—NH₂, or—O—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is, independently, 1 to 4; or apharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula II:

wherein: R₁ is H; R₂ is —NH₂; each R¹¹ is, independently, —(CH₂)₀₋₄—R⁴where R⁴ is chosen from hydrogen, —C₁-C₄alkyl, —C₃-C₁₂branched alkyl,—C₃-C₈cycloalkyl, phenyl optionally substituted with one or more—C₁-C₄alkyl groups, —C₁-C₄alkoxy groups, or halo groups, and heteroaryloptionally substituted with one or more —C₁-C₄alkyl groups, —C₁-C₄alkoxygroups, or halo groups; each R₉ is, independently, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, or —(CH₂)_(q)—V where q is from 1to 5, and each V is, independently, chosen from amino, hydroxyl,—C₁-C₆alkylamino, —C₁-C₆dialkylamino, —C₁-C₆alkylurea, —NH(CH₂)₁₋₄NH₂,—N(CH₂CH₂NH₂)₂, amidine, guanidine, semicarbazone, imidazole,piperidine, piperazine, 4-alkylpiperazine, phenyl optionally substitutedwith an amino, —C₁-C₆alkylamino, or —C₁-C₆dialkylamino, and loweracylamino optionally substituted with one or more amino, loweralkylamino, or lower dialklylamino, where the alkylene chain isoptionally substituted with an amino or hydroxyl group; and m is 2 to atleast about 30; or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula III:

wherein:

X is —C(R⁷)C(R⁸), —C(═O), N(R⁹), O, S, S(═O), or S(═O)₂;

R⁷, R⁸, and R⁹ are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo,—OH, —CF₃, aromatic group, —(CH₂)_(q)NH₂, or —(CH₂)_(q)NHC(═NH)NH₂,where q is 0 to 4;

R¹ and R² are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo, OH,-haloC₁-C₈alkyl, —CN, or —CF₃;

R³ and R⁴ are, independently, H or -carbocycle(R⁵)(R⁶);

each R⁵ and each R⁶ are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy,halo, amino, —OH, —CF₃, —O—(CH₂)_(p)—NH₂, —O—(CH₂)_(p)NHC(═NH)NH₂,—S—(CH₂)_(p)—NH₂, —N((CH₂)_(p)NH₂)₂, —S—(CH₂)_(p)NHC(═NH)NH₂,—C(═O)NH(CH₂)_(p)NH₂, —(CH₂)_(p)N((CH₂)_(p)NH₂)₂, where each p is,independently, 1 to 5, aromatic group, heterocycle, or the free base orsalt form of —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 8;

provided that the compound is not Compound 116-134;

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula IV;

wherein;

R¹ and R² are, independently, —C(═NH)NH₂, —(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═NH)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula V:

wherein:

R¹ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R² is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —C═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula VI:

wherein:

R¹ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R² is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R³ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4; and

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula VII:

wherein:

each R¹ is, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo, —OH, —CF₃, or —CN; and

each R² is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4; or a pharmaceutically acceptablesalt thereof.

The present disclosure also provides compounds of Formula VIII:

wherein:

R¹ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R² is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂, or—C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R³ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂, or—C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁴ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —CH═CH—(CH₂)₂NC(═N)NH₂,—C≡C—CH₂NH₂, —C≡C—CH₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂, or—C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁵ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —C≡C—CH₂NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁶ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂, or—C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁷ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁸ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—CH₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂, or—C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4; and

R⁹ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂, or—C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula IX:

wherein:

each X is, independently, O or S;

each Y is, independently, O or S;

each R₂ is, independently, —C₁-C₉ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

each R₃ is, independently, —C₁-C₉ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; and

each R₄ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where n is an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula X:

wherein:

X is

and

each R¹ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where n is an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides pharmaceutical compositionscomprising any one or more of the foregoing compounds, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

The present disclosure also provides methods of killing or inhibitingthe growth of a Candida or Aspergillus species comprising contacting theCandida or Aspergillus species with any one or more of the foregoingcompounds, or pharmaceutically acceptable salt thereof.

The present disclosure also provides methods of preventing or treating amammal having candidiasis (oral and/or disseminated) and/or anaspergillus infection comprising administering to the mammal in needthereof an effective amount of any one or more of the foregoingcompounds, or pharmaceutically acceptable salt thereof.

The present disclosure also provides any one or more of the foregoingcompounds, or pharmaceutically acceptable salts thereof, for killing orinhibiting the growth of a Candida or Aspergillus species or preventingor treating a mammal having candidiasis (oral and/or disseminated)and/or an aspergillus infection.

The present disclosure also provides any one or more of the foregoingcompounds, or pharmaceutically acceptable salts thereof, for use in themanufacture of a medicament for killing or inhibiting the growth of aCandida or Aspergillus species or preventing or treating a mammal havingcandidiasis (oral and/or disseminated) and/or an aspergillus infection.

The present disclosure also provides uses of any one or more of theforegoing compounds, or pharmaceutically acceptable salts thereof, forkilling or inhibiting the growth of a Candida or Aspergillus species orpreventing or treating a mammal having candidiasis (oral and/ordisseminated) and/or an aspergillus infection.

The present disclosure also provides uses of any one or more of theforegoing compounds, or pharmaceutically acceptable salts thereof, inthe manufacture of a medicament for killing or inhibiting the growth ofa Candida or Aspergillus species or preventing or treating a mammalhaving candidiasis (oral and/or disseminated) and/or an aspergillusinfection.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows results of screening over 800 compounds at a singleconcentration of 10μM against a clinical isolate of C. albicans GDH2346(triangles), and an additional 400 compounds with 11 concentrations togive an IC₅₀ (see, green squares).

FIGS. 2A, 2B, 2C, and 2D show results of fluorescence microscopy of C.albicans (GDH2346) hyphae treated with Compound 100 (8 μg/mL) for 0minutes (FIG. 2A), 15 minutes (FIG. 2B), 30 minutes (FIG. 2C), or 60minutes (FIG. 2D).

FIGS. 3A and 3B show results of dose-dependent membrane permeabilizationof Candida, resulting in cellular accumulation of PI evident within 30minutes at 8 to 32 μg/mL Compound 100 concentrations (FIG. 3A) andpermeabilized after a 5-minute treatment with Compound 100 at 32 μg/mL(FIG. 3B).

FIGS. 4A, 4B, and 4C show results of cells treated with either Compound100 or Histatin 5; levels of intracellular and extracellular ATP incells (FIG. 4A); time-frame of ATP efflux following treatment (FIG. 4B);and dose-dependent efflux over 30 minutes of exposure time (FIG. 4C).

FIGS. 5A and 5B show results of sterilization of infected tonguefollowing a single topical dose of Compound 100 or Nystatin (FIG. 5A);and a photomicrograph of a 10 μm section of a tongue from an infectedmouse on day 4, stained with PAS (FIG. 5B).

FIGS. 6A and 6B show cidal activity with rapid killing kinetics ofCompound 100 (FIG. 6A) and Compound 135 (FIG. 6B).

FIG. 7 shows results of cidal activity of Compound 135 with ≧1.5 log₁₀reductions in tissue burden from treatment onset.

FIG. 8 shows results of static activity with current triazole andanti-fungals in a model.

FIG. 9 shows survival of mice over a 14-day period in a disseminatedCandidiasis survival study model in which neutropenic mice inoculatedwith C. albicans in a tail vein.

DESCRIPTION OF EMBODIMENTS

The identification of a potent HDP mimetic (Compound 100), inter alia,that exhibits rapid membrane-disrupting activity against Candidaalbicans at low concentrations, using propidium iodide uptake isdemonstrated here. In contrast to Histatin 5, Compound 100 treatmentresulted in rapid efflux of ATP, and killing occurred even in thepresence of sodium azide, which prevents membrane transport.Fluorescence microscopy, however, showed incorporation of the compoundinto the cells, suggesting a mechanism of self-promoted uptake. Thecompound also demonstrated a significant reduction of metabolic activityin mature biofilms of C. albicans grown at an air-liquid interface. Toexamine the activity of Compound 100 in vivo, an oral model of Candidainfection was established in C57BI/6 mice. Animals were first treatedfor 5 days with oral tetracycline to reduce normal oral flora. Aninfection was initiated in the mice by inoculating a 50 μL suspension ofC. albicans onto lightly scored tongues. This led to colonization of thetongues by days 2 to 4 after inoculation as measured by histologicalanalysis and by recovery of viable colonies upon homogenization. Topicaltreatment of the infections on day 3 with a single 50 μL dose of a 1mg/mL compound solution in a neutral hydrogel was sufficient to reducethe total colony counts by greater than 10-fold, equivalent to a similartreatment with an equivalent concentration of Nystatin suspension. Theseresults, as well as those presented herein, suggest that the compoundsdescribed herein represent a strong potential source of fungicidaldrugs.

Unless defined otherwise, all technical and scientific terms have thesame meaning as is commonly understood by one of ordinary skill in theart to which the embodiments disclosed belongs.

As used herein, the terms “a” or “an” means that “at least one” or “oneor more” unless the context clearly indicates otherwise.

As used herein, the term “about” means that the numerical value isapproximate and small variations would not significantly affect thepractice of the disclosed embodiments. Where a numerical limitation isused, unless indicated otherwise by the context, “about” means thenumerical value can vary by ±10% and remain within the scope of thedisclosed embodiments.

As used herein, the term “acylamino” means an amino group substituted byan acyl group (e.g., —O—C(═O)—H or —O—C(═O)-alkyl. An example of anacylamino is —NHC(═O)H or —NHC(═O)CH₃. The term “lower acylamino” refersto an amino group substituted by a lower acyl group (e.g., —O—C(═O)—H or—O—C(═O)—C₁₋₆alkyl). An example of a lower acylamino is —NHC(═O)H or—NHC(═O)CH₃.

As used herein, the term “alkenyl” means a straight or branched alkylgroup having one or more double carbon-carbon bonds and 2-20 carbonatoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. In someembodiments, the alkenyl chain is from 2 to 10 carbon atoms in length,from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length,or from 2 to 4 carbon atoms in length.

As used herein, the term “alkoxy” means a straight or branched —O-alkylgroup of 1 to 20 carbon atoms, including, but not limited to, methoxy,ethoxy, n-propoxy, isopropoxy, t-butoxy, and the like. In someembodiments, the alkoxy chain is from 1 to 10 carbon atoms in length,from 1 to 8 carbon atoms in length, from 1 to 6 carbon atoms in length,from 1 to 4 carbon atoms in length, from 2 to 10 carbon atoms in length,from 2 to 8 carbon atoms in length.

As used herein, the term“alkyl” means a saturated hydrocarbon groupwhich is straight-chained or branched. An alkyl group can contain from 1to 20, from 2 to 20, from 1 to 10, from 2 to 10, from 1 to 8, from 2 to8, from 1 to 6, from 2 to 6, from 1 to 4, from 2 to 4, from 1 to 3, or 2or 3 carbon atoms. Examples of alkyl groups include, but are not limitedto, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl),butyl (e.g., n-butyl, t-butyl, isobutyl), pentyl (e.g., n-pentyl,isopentyl, neopentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl,octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl,2,2-dimethyl-1-propyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, and thelike.

As used herein, the term “alkylamino” means an amino group substitutedby an alkyl group having from 1 to 6 carbon atoms. An example of analkylamino is —NHCH₂CH₃.

As used herein, the term “alkylene” or “alkylenyl” means a divalentalkyl linking group. An example of an alkylene (or alkylenyl) ismethylene or methylenyl (—CH₂—).

As used herein, the term “alkylthio” means an —S-alkyl group having from1 to 6 carbon atoms. An example of an alkylthio group is —SCH₂CH₃.

As used herein, the term “alkynyl” means a straight or branched alkylgroup having one or more triple carbon-carbon bonds and 2-20 carbonatoms, including, but not limited to, acetylene, 1-propylene,2-propylene, and the like. In some embodiments, the alkynyl chain is 2to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.

As used herein, the term “amidino” means —C(═NH)NH₂.

As used herein, the term “amino” means —NH₂.

As used herein, the term “aminoalkoxy” means an alkoxy group substitutedby an amino group. An example of an aminoalkoxy is —OCH₂CH₂NH₂.

As used herein, the term “aminoalkyl” means an alkyl group substitutedby an amino group. An example of an aminoalkyl is —CH₂CH₂NH₂.

As used herein, the term “aminosulfonyl” means —S(═O)₂NH₂.

As used herein, the term “aminoalkylthio” means an alkylthio groupsubstituted by an amino group. An example of an aminoalkylthio is—SCH₂CH₂NH₂.

As used herein, the term “amphiphilic” means a three-dimensionalstructure having discrete hydrophobic and hydrophilic regions. Anamphiphilic compound suitably has the presence of both hydrophobic andhydrophilic elements.

As used herein, the term “animal” includes, but is not limited to,humans and non-human vertebrates such as wild, domestic, and farmanimals.

As used herein, the phrase “an effective amount” of a compound can bemeasured by the effectiveness of the compound. In some embodiments, aneffective amount inhibits growth of a particular Candida or Aspergillusspecies by at least 10%, by at least 20%, by at least 30%, by at least40%, by at least 50%, by at least 60%, by at least 70%, by at least 80%,by at least 90%, or by at least 95%. In some embodiments, “an effectiveamount” is also a “therapeutically effective amount” whereby thecompound reduces or eliminates at least one harmful effect of a Candidaor Aspergillus species on a mammal.

As used herein, the term “aryl” means a monocyclic, bicyclic, orpolycystic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons.In some embodiments, aryl groups have from 6 to 20 carbon atoms or from6 to 10 carbon atoms. Examples of aryl groups include, but are notlimited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl,indenyl, tetrahydronaphthyl, and the like.

As used herein, the term “arylalkyl” means a C₁₋₆alkyl substituted byaryl.

As used herein, the term “arylamino” means an amino group substituted byan aryl group. An example of an arylamino is —NH(phenyl).

As used herein, the term “arylene” means an aryl linking group, i.e. anaryl group that links one group to another group in a molecule.

As used herein, the term “candidiasis” means a yeast infection of aCandida species. Types of candidiasis include, local infections such as,for example, oral thrush or oral candidiasis, genital candidiasis,intertrigo, paronychia, and onychomycosis, as well as disseminated,candidiasis.

As used herein, the term “carbocycle” means a 5- or 6-membered,saturated or unsaturated cyclic ring, optionally containing O, S, or Natoms as part of the ring. Examples of carbocycles include, but are notlimited to, cyclopentyl, cyclohexyl, cyclopenta-1,3-diene, phenyl, andany of the heterocycles recited above.

As used herein, the term “carrier” means a diluent, adjuvant, orexcipient with which a compound is administered. Pharmaceutical carrierscan be liquids, such as water and oils, including those of petroleum,animal, vegetable or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil and the like. The pharmaceutical carriers canalso be saline, gum acacia, gelatin, starch paste, talc, keratin,colloidal silica, urea, and the like. In addition, auxiliary,stabilizing, thickening, lubricating and coloring agents can be used.

As used herein, the term “chemically nonequivalent termini” means afunctional group such as an ester, amide, sufonamide, or N-hydroxyoximethat, when reversing the orientation of the functional group (e.g.,—(C═O)O—) produces different chemical entities (e.g., —R¹C(═O)OR²- vs.-R¹OC(═O)R²-).

As used herein, the term, “compound” means all stereoisomers, tautomers,and isotopes of the compounds described herein.

As used herein, the terms “comprising” (and any form of comprising, suchas “comprise”, “comprises”, and “comprised”), “having” (and any form ofhaving, such as “have” and “has”), “including” (and any form ofincluding, such as “includes” and “include”), or “containing” (and anyform of containing, such as “contains” and “contain”), are inclusive oropen-ended and do not exclude additional, unrecited elements or methodsteps.

As used herein, the term “cyano” means —CN.

As used herein, the term “cycloalkyl” means non-aromatic cyclichydrocarbons including a cyclized alkyl, alkenyl, and alkynyl groupsthat contain up to 20 ring-forming carbon atoms. Cycloalkyl groups caninclude mono- or polycyclic ring systems such as fused ring systems,bridged ring systems, and spiro ring systems. In some embodiments,polycyclic ring systems include 2, 3 or 4 fused rings. A cycloalkylgroup can contain from 3 to 15, from 3 to 10, from 3 to 8, from 3 to 6,from 4 to 6, from 3 to 5, or 5 or 6 ring-forming carbon atoms.Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido. Examples of cycloalkyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl,norcarnyl, adamantyl, and the like. Also included in the definition ofcycloalkyl are moieties that have one or more aromatic rings fused(having a bond in common with) to the cycloalkyl ring, for example,benzo or thienyl derivatives of pentane, pentene, hexane, and the like(e.g., 2,3-dihydro-1H-indene-1-yl, or 1H-inden-2(3H)-one-1-yl).

As used herein, the term“dialkylamino” means an amino group substitutedby two alkyl groups, each having from 1 to 6 carbon atoms.

As used herein, the term “facially amphiphilic” or “facialamphiphilicity” means compounds with polar (hydrophilic) and nonpolar(hydrophobic) side chains that adopt conformation(s) leading tosegregation of polar and nonpolar side chains to opposite faces orseparate regions of the structure or molecule.

As used herein, the phrase “groups with chemically nonequivalenttermini” means functional groups such as esters amides, sulfonamides andN-hydroxyoximes where reversing the orientation of the substituents,e.g. R¹C(═O)OR² vs. R¹O(O═)CR², produces unique chemical entities.

As used herein, the term “guanidino” means —NH(═NH)NH₂.

As used herein, the term “halo” means halogen groups including, but notlimited to fluoro, chloro, bromo, and iodo.

As used herein, the term “haloalkoxy” means an —O-haloalkyl group. Anexample of an haloalkoxy group is OCF₃.

As used herein, the term “haloalkyl” means a C₁₋₆alkyl group having oneor more halogen substituents. Examples of haloalkyl groups include, butare not limited to, —CF₃, —C₂F₅, —CHF₂, —CCl₃, —CHCl₂, —C₂Cl₅, —CH₂CF₃,and the like.

As used herein, the term “heteroaryl” means an aromatic heterocyclehaving up to 20 ring-forming atoms (e.g., C) and having at least oneheteroatom ring member (ring-forming atom) such as sulfur, oxygen, ornitrogen. In some embodiments, the heteroaryl group has at least one ormore heteroatoms ring-forming atoms, each of which are, independently,sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl grouphas from 3 to 20 ring-forming atoms, from 3 to 10 ring-forming atoms,from 3 to 6 ring-forming atoms, or from 3 to 5 ring-forming atoms. Insome embodiments, the heteroaryl group contains 2 to 14 carbon atoms,from 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments,the heteroaryl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic(e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroarylgroups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl,imidazolyl, thiazolyl, indolyl (such as indol-3-yl), pyrryl, oxazolyl,benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl,triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyranyl,oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, pyrazolyl,indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl,2H-pyrrolyl, pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl,naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl,furazanyl, phenoxazinyl groups, and the like. Suitable heteroaryl groupsinclude 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole,imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine,and 2-aminopyridine.

As used herein, the term “heteroarylalkyl” means a C₁₋₆alkyl groupsubstituted by a heteroaryl group.

As used herein, the term “heteroarylamino” means an amino groupsubstituted by a heteroaryl group. An example of a heteroarylamino is—NH-(2-pyridyl).

As used herein, the term “heteroarylene” means a heteroaryl linkinggroup, i.e., a heteroaryl group that links one group to another group ina molecule.

As used herein, the term “heterocycle” or “heterocyclic ring” means a 5-to 7-membered mono- or bicyclic or 7- to 10-membered bicyclicheterocyclic ring system any ring of which may be saturated orunsaturated, and which consists of carbon atoms and from one to threeheteroatoms chosen from N, O and S, and wherein the N and S heteroatomsmay optionally be oxidized, and the N heteroatom may optionally bequaternized, and including any bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring.Particularly useful rings containing one oxygen or sulfur, one to threenitrogen atoms, or one oxygen or sulfur combined with one or twonitrogen atoms. The heterocyclic ring may be attached at any heteroatomor carbon atom which results in the creation of a stable structure.Examples of heterocyclic groups include, but are not limited to,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl,pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl,imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same asmorpholinyl.

As used herein, the term “heterocycloalkyl” means non-aromaticheterocycles having up to 20 ring-forming atoms including cyclizedalkyl, alkenyl, and alkynyl groups, where one or more of thering-forming carbon atoms is replaced by a heteroatom such as O, N, or Satom. Hetercycloalkyl groups can be mono or polycyclic (e.g., fused,bridged, or spiro systems). In some embodiments, the heterocycloalkylgroup has from 1 to 20 carbon atoms, or from 3 to 20 carbon atoms. Insome embodiments, the heterocycloalkyl group contains 3 to 14ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6 ring-formingatoms. In some embodiments, the heterocycloalkyl group has 1 to 4heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In someembodiments, the heterocycloalkyl group contains 0 to 3 double bonds. Insome embodiments, the heterocycloalkyl group contains 0 to 2 triplebonds. Examples of heterocycloalkyl groups include, but are not limitedto, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole,benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl,oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl,imidazolidinyl, pyrrolidin-2-one-3-yl, and the like. In addition,ring-forming carbon atoms and heteroatoms of a heterocycloalkyl groupcan be optionally substituted by oxo or sulfido. For example, aring-forming S atom can be substituted by 1 or 2 oxo (form a S(O) orS(O)₂). For another example, a ring-forming C atom can be substituted byoxo (form carbonyl). Also included in the definition of heterocycloalkylare moieties that have one or more aromatic rings fused (having a bondin common with) to the nonaromatic heterocyclic ring including, but notlimited to, pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, andbenzo derivatives of heterocycles such as indolene, isoindolene,4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl,5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, isoindolin-1-one-3-yl,and 3,4-dihydroisoquinolin-1(2H)-one-3yl groups. Ring-forming carbonatoms and heteroatoms of the heterocycloalkyl group can be optionallysubstituted by oxo or sulfido.

As used herein, the term “hydroxy” or “hydroxyl” means an —OH group.

As used herein, the term “hydroxyalkyl” or “hydroxylalkyl” means analkyl group substituted by a hydroxyl group. Examples of a hydroxyalkylinclude, but are not limited to, —CH₂OH and —CH₂CH₂OH.

As used herein, the term “individual” or “patient,” usedinterchangeably, means any animal, including mammals, such as mice,rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses,or primates, such as humans.

As used herein, the phrase “inhibiting the growth” means reducing by anymeasurable amount the growth of one or more yeast or mold, such as aCandida or Aspergillus species. In some embodiments, the inhibition ofgrowth may result in cell death of the yeast or mold.

As used herein, the phrase “in need thereof” means that the animal ormammal has been identified as having a need for the particular method ortreatment. In some embodiments, the identification can be by any meansof diagnosis. In any of the methods and treatments described herein, theanimal or mammal can be in need thereof. In some embodiments, the animalor mammal is in an environment or will be traveling to an environment inwhich a particular disease, disorder, or condition is prevelant.

As used herein, the phrase “integer from 1 to 5” means 1, 2, 3, 4, or 5.

As used herein, the term “isolated” means that the compounds describedherein are separated from other components of either (a) a naturalsource, such as a plant or cell, such as a bacterial culture, or (b) asynthetic organic chemical reaction mixture, such as by conventionaltechniques.

As used herein, the term “mammal” means a rodent (i.e., a mouse, a rat,or a guinea pig), a monkey, a cat, a dog, a cow, a horse, a pig, or ahuman. In some embodiments, the mammal is a human.

As used herein, the term“nitro” means —NO₂.

As used herein, the term “n-membered”, where n is an integer, typicallydescribes the number of ring-forming atoms in a moiety, where the numberof ring-forming atoms is n. For example, pyridine is an example of a6-membered heteroaryl ring and thiophene is an example of a 5-memberedheteroaryl ring.

As used used herein, the phrase “optionally substituted” means thatsubstitution is optional and therefore includes both unsubstituted andsubstituted atoms and moieties. A “substituted” atom or moiety indicatesthat any hydrogen on the designated atom or moiety can be replaced witha selection from the indicated substituent groups, provided that thenormal valency of the designated atom or moiety is not exceeded, andthat the substitution results in a stable compound. For example, if amethyl group is optionally substituted, then 3 hydrogen atoms on thecarbon atom can be replaced with substituent groups.

As used herein, the phrase “pharmaceutically acceptable” means thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith tissues of humans and animals. In some embodiments,“pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopeia orother generally recognized pharmacopeia for use in animals, and moreparticularly in humans.

As used herein, the phrase “pharmaceutically acceptable salt(s),”includes, but is not limited to, salts of acidic or basic groups.Compounds that are basic in nature are capable of forming a wide varietyof salts with various inorganic and organic acids. Acids that may beused to prepare pharmaceutically acceptable acid addition salts of suchbasic compounds are those that form non-toxic acid addition salts, i.e.,salts containing pharmacologically acceptable anions including, but notlimited to, sulfuric, thiosulfuric, citric, maleic, acetic, oxalic,hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate,lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, bicarbonate, malonate, mesylate, esylate,napsydisylate, tosylate, besylate, orthophoshate, trifluoroacetate, andpamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.Compounds that include an amino moiety may form pharmaceuticallyacceptable salts with various amino acids, in addition to the acidsmentioned above. Compounds that are acidic in nature are capable offorming base salts with various pharmacologically acceptable cations.Examples of such salts include, but are not limited to, alkali metal oralkaline earth metal salts and, particularly, calcium, magnesium,ammonium, sodium, lithium, zinc, potassium, and iron salts. The presentdisclosure also includes quaternary ammonium salts of the compoundsdescribed herein, where the compounds have one or more tertiary aminemoiety.

As used herein, the term “phenyl” means —C₆H₅. A phenyl group can beunsubstituted or substituted with one, two, or three suitablesubstituents.

As used herein, the terms “prevention” or “preventing” mean a reductionof the risk of acquiring a particular disease, condition, or disorder.

As used herein, the term “prodrug” means a derivative of a known directacting drug, which derivative has enhanced delivery characteristics andtherapeutic value as compared to the drug, and is transformed into theactive drug by an enzymatic or chemical process.

As used herein, the term “purified” means that when isolated, theisolate contains at least 90%, at least 95%, at least 98%, or at least99% of a compound described herein by weight of the isolate.

As used herein, the phrase “quaternary ammonium salts” means derivativesof the disclosed compounds with one or more tertiary amine moietieswherein at least one of the tertiary amine moieties in the parentcompound is modified by converting the tertiary amine moiety to aquaternary ammonium cation via alkylation (and the cations are balancedby anions such as Cl⁻, CH₃COO⁻, and CF₃COO⁻), for example methylation orethylation.

As used herein, the term “semicarbazone” means ═NNHC(═O)NH₂.

As used herein, the phrase “solubilizing agent” means agents that resultin formation of a micellar solution or a true solution of the drug.

As used herein, the term “solution/suspension” means a liquidcomposition wherein a first portion of the active agent is present insolution and a second portion of the active agent is present inparticulate form, in suspension in a liquid matrix.

As used herein, the phrase “substantially isolated” means a compoundthat is at least partially or substantially separated from theenvironment in which it is formed or detected.

As used herein, the phrase “suitable substituent” or “substituent” meansa group that does not nullify the synthetic or pharmaceutical utility ofthe compounds described herein or the intermediates useful for preparingthem. Examples of suitable substituents include, but are not limited to:—C₁-C₆alkyl, —C₁-C₆alkenyl, —C₁-C₆alkynyl, —C₅-C₆aryl, —C₁-C₆alkoxy,—C₃-C₅heteroaryl, —C₃-C₆cycloalkyl, —C₅-C₆aryloxy, —CN, —OH, oxo, halo,haloalkyl, —NO₂, —C(═O)OH, —NH₂, —NH(C₁-C₈alkyl), —N(C₁-C₈alkyl)₂,—NH(C₆aryl), —N(C₅-C₆aryl)₂, —C(═O)H, —C(═O)(C₁-C₆alkyl),—C(═O)(C₅-C₆aryl), —C(═)—O—((C₁-C₆)alkyl), and —C(═O)—O—((C₅-C₆)aryl.Any of the compounds herein may be further substituted at, for example,open positions (such as on a ring structure) by any of thesesubstituents as desired by one skilled in the art. One of skill in artcan readily choose a suitable substituent based on the stability andpharmacological and synthetic activity of the compounds describedherein.

As used herein, the phrase “therapeutically effective amount” means theamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician. The therapeutic effect is dependentupon the disorder being treated or the biological effect desired. Assuch, the therapeutic effect can be a decrease in the severity ofsymptoms associated with the disorder and/or inhibition (partial orcomplete) of progression of the disorder, or improved treatment,healing, prevention or elimination of a disorder, or side-effects. Theamount needed to elicit the therapeutic response can be determined basedon the age, health, size and sex of the subject. Optimal amounts canalso be determined based on monitoring of the subject's response totreatment.

As used herein, the terms “treat,” “treated,” or “treating” mean boththerapeutic treatment and prophylactic or preventative measures whereinthe object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder or disease, or obtain beneficial ordesired clinical results. For purposes herein, beneficial or desiredclinical results include, but are not limited to, alleviation ofsymptoms; diminishment of extent of condition, disorder or disease;stabilized (i.e., not worsening) state of condition, disorder ordisease; delay in onset or slowing of condition, disorder or diseaseprogression; amelioration of the condition, disorder or disease state orremission (whether partial or total), whether detectable orundetectable; an amelioration of at least one measurable physicalparameter, not necessarily discernible by the patient; or enhancement orimprovement of condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment.

At various places in the present specification, substituents ofcompounds may be disclosed in groups or in ranges. It is specificallyintended that the disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆alkyl” is specifically intended to individually disclosemethyl, ethyl, propyl, C₄alkyl, C₅alkyl, and C₆alkyl.

For compounds in which a variable appears more than once, each variablecan be a different moiety selected from the Markush group defining thevariable. For example, where a structure is described having two Rgroups that are simultaneously present on the same compound, the two Rgroups can represent different moieties selected from the Markush groupsdefined for R. In another example, when an optionally multiplesubstituent is designated in the form, for example,

then it is understood that substituent R can occur s number of times onthe ring, and R can be a different moiety at each occurrence. Further,in the above example, where the variable T¹ is defined to includehydrogens, such as when T¹ is CH₂, NH, etc., any H can be replaced witha suitable substituent.

It is further appreciated that certain features of the disclosure, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the disclosure which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

It is understood that the present disclosure encompasses the use, whereapplicable, of stereoisomers, diastereomers and optical stereoisomers ofthe compounds described herein, as well as mixtures thereof.Additionally, it is understood that stereoisomers, diastereomers, andoptical stereoisomers of the compounds described herein, and mixturesthereof, are within the scope of the present disclosure. By way ofnon-limiting example, the mixture may be a racemate or the mixture maycomprise unequal proportions of one particular stereoisomer over theother. Additionally, the compounds can be provided as a substantiallypure stereoisomers, diastereomers and optical stereoisomers (such asepimers).

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended to be included within the scope of thepresent disclosure unless otherwise indicated. Compounds that containasymmetrically substituted carbon atoms can be isolated in opticallyactive or racemic forms. Methods of preparation of optically activeforms from optically active starting materials are known in the art,such as by resolution of racemic mixtures or by stereoselectivesynthesis. Many geometric isomers of olefins, C═N double bonds, and thelike can also be present in the compounds described herein, and all suchstable isomers are contemplated in the present disclosure. Cis and transgeometric isomers of the compounds are also included within the scope ofthe disclosure and can be isolated as a mixture of isomers or asseparated isomeric forms. Where a compound capable of stereoisomerism orgeometric isomerism is designated in its structure or name withoutreference to specific R/S or cis/trans configurations, it is intendedthat all such isomers are contemplated.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art, including, for example, fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods include, but are not limited to,optically active acids, such as the D and L forms of tartaric acid,diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malicacid, lactic acid, and the various optically active camphorsulfonicacids such as β-camphorsulfonic acid. Other resolving agents suitablefor fractional crystallization methods include, but are not limited to,stereoisomerically pure forms of α-methylbenzylamine (e.g., S and Rforms, or diastereomerically pure forms), 2-phenylglycinol,norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures canalso be carried out by elution on a column packed with an opticallyactive resolving agent (e.g., dinitrobenzoylphenylglycine). Suitableelution solvent compositions can be determined by one skilled in theart.

Compounds may also include tautomeric forms. Tautomeric forms resultfrom the swapping of a single bond with an adjacent double bond togetherwith the concomitant migration of a proton. Tautomeric forms includeprototropic tautomers which are isomeric protonation states having thesame empirical formula and total charge. Examples of prototropictautomers include, but are not limited to, ketone-enol pairs,amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs,enamine-imine pairs, and annular forms where a proton can occupy two ormore positions of a heterocyclic system including, but not limited to,1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds also include hydrates and solvates, as well as anhydrous andnon-solvated forms.

Compounds can also include all isotopes of atoms occurring in theintermediates or final compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. For example, isotopesof hydrogen include tritium and deuterium.

In some embodiments, the compounds, or salts thereof, are substantiallyisolated. Partial separation can include, for example, a compositionenriched in the compound described herein. Substantial separation caninclude compositions containing at least about 50%, at least about 60%,at least about 70%, at least about 80%, at least about 90%, at leastabout 95%, at least about 97%, or at least about 99% by weight of thecompound, or salt thereof. Methods for isolating compounds and theirsalts are routine in the art.

Although the disclosed compounds are suitable, other functional groupscan be incorporated into the compound with an expectation of similarresults. In particular, thioamides and thioesters are anticipated tohave very similar properties. The distance between aromatic rings canimpact the geometrical pattern of the compound and this distance can bealtered by incorporating aliphatic chains of varying length, which canbe optionally substituted or can comprise an amino acid, a dicarboxylicacid or a diamine. The distance between and the relative orientation ofmonomers within the compounds can also be altered by replacing the amidebond with a surrogate having additional atoms. Thus, replacing acarbonyl group with a dicarbonyl alters the distance between themonomers and the propensity of dicarbonyl unit to adopt an antiarrangement of the two carbonyl moiety and alter the periodicity of thecompound. Pyromellitic anhydride represents still another alternative tosimple amide linkages which can alter the conformation and physicalproperties of the compound. Modern methods of solid phase organicchemistry (E. Atherton and R. C. Sheppard, Solid Phase Peptide SynthesisA Practical Approach IRL Press Oxford 1989) now allow the synthesis ofhomodisperse compounds with molecular weights approaching 5,000 Daltons.Other substitution patterns are equally effective.

The compounds also include derivatives referred to as prodrugs, whichcan be prepared by modifying functional groups present in the compoundsin such a way that the modifications are cleaved, either in routinemanipulation or in vivo, to the parent compounds. Examples of prodrugsinclude compounds as described herein that contain one or more molecularmoieties appended to a hydroxyl, amino, sulfhydryl, or carboxyl group ofthe compound, and that when administered to a patient, cleaves in vivoto form the free hydroxyl, amino, sulfhydryl, or carboxyl group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of alcohol and aminefunctional groups in the compounds described herein. Preparation and useof prodrugs is discussed in T. Higuchi et al., “Pro-drugs as NovelDelivery Systems,” Vol. 14 of A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference in their entireties.

Some of the compounds may be capable of adopting amphiphilicconformations that allow for the segregation of polar and nonpolarregions of the molecule into different spatial regions and provide thebasic for a number of uses.

Compounds containing an amine function can also form N-oxides. Areference herein to a compound that contains an amine function alsoincludes the N-oxide. Where a compound contains several amine functions,one or more than one nitrogen atom can be oxidized to form an N-oxide.Examples of N-oxides include N-oxides of a tertiary amine or a nitrogenatom of a nitrogen-containing heterocycle. N-Oxides can be formed bytreatment of the corresponding amine with an oxidizing agent such ashydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid) (see,Advanced Organic Chemistry, by Jerry March, 4th Edition, WileyInterscience).

The structures depicted herein may omit one or more necessary hydrogenatoms to complete the appropriate valency. Thus, in some instances acarbon atom or nitrogen atom, for example, may appear to have an openvalency (i.e., a carbon atom with only two bonds showing wouldimplicitly also be bonded to two hydrogen atoms; in addition, a nitrogenatom with a single bond depicted would implicitly also be bonded to twohydrogen atoms). For example, “—N” would be considered by one skilled inthe art to be “—NH₂.” Thus, in any structure depicted herein wherein avalency is open, one or more hydrogen atoms is implicit, and is onlyomitted for brevity.

The present disclosure provides compounds of Formula I:

wherein:

each X is, independently, O, S, or S(═O)₂;

each R¹ is, independently, —CH₃, —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴, where each n is,independently, 1 to 4, and each R⁴ is, independently, H, —C₁-C₃alkyl, or—(CH₂)_(p)—NH₂, where each p is, independently, 1 or 2;

each R² is, independently, H, halo, —CF₃, or —C(CH₃)₃;

each V² is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where eachn is, independently, 1 to 4; or each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; and

each R⁶ is H, —S—(CH₂)_(m)—NH₂, —S—(CH₂)_(m)—NH—C(═NH)NH₂,—O—(CH₂)_(m)—NH₂, or —O—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is,independently, 1 to 4;

or a pharmaceutically acceptable salt thereof, provided that thecompound is not:

In some embodiments, each X is S.

In any of the above embodiments, each R¹ is, independently, —CH₃,—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴,where each n is, independently, 1 or 2, and each R⁴ is, independently, Hor methyl; or each R¹ is, independently, —CH₃, —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴, where each n is 2and each R⁴ is H; or each R¹ is, independently, —CH₃, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2; or each R¹ is —CH₃,—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2; or eachR¹ is —CH₃ or —(CH₂)_(n)—NH₂ where each n is 2.

In any of the above embodiments, each R² is, independently, H, Br, F,Cl, —CF₃, or —C(CH₃)₃; or each R² is, independently, Br, F, Cl, —CF₃, or—C(CH₃)₃; or each R² is —CF₃.

In any of the above embodiments, each V² is H and each V¹ is,independently, —N—C(═O)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each V² is H and each V¹ is, independently,—N—C(═O)—R³, where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 or 2; or eachV² is H and each V¹ is, indpendently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis 2; or each V² is H and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where n is 2.

In any of the above embodiments, each V¹ is H and each V² is,independently, —S—R⁵, where R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachV¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis 1 or 2; or each V¹ is H and each V² is, independently, —S—R⁵, whereeach R⁵ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 2; or each V¹ is H and each V² is —S—R⁵, where each R⁵is —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2; or eachV¹ is H and each V² is —S—R⁵, where each R⁵ is —(CH₂)_(n)—NH₂ where eachn is 2.

In any of the above embodiments, each R⁶ is H, —S—(CH₂)_(m)—NH₂, or—S—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is, independently, 1 to 4; oreach R⁶ is H, —S—(CH₂)_(m)—NH₂, or —S—(CH₂)_(m)—NH—C(═NH)NH₂, where eachm is, independently, 1 or 2; or each R⁶ is H or—S—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is, independently, 1 or 2; oreach R⁶ is H or —S—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is 2.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, —CF₃, or—C(CH₃)₃; and each V¹ is H and each V² is, independently, —S—R⁵, whereeach R⁵ is, independently, —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R² is,independently, —CF₃ or —C(CH₃)₃; and each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂,where each n is, independently, 1 or 2.

In some embodiments, each X is S; each R¹ is —(CH₂)_(n)—NH₂, where eachn is 1 or 2; each R² is, independently, —CF₃ or —C(CH₃)₃; and each V¹ isH and each V² is —S—R⁵, where each R⁵ is —(CH₂)_(n)—NH₂, where each n is1 or 2.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴,where each n is, independently, 1 to 4, and each R⁴ is, independently, Hor methyl; each R² is, independently, halo, —CF₃, or —C(CH₃)₃; and eachV² is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 or 2, and eachR⁴ is, independently, H or methyl; each R² is, independently, halo; andeach V² is H, and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, —CF₃, or—C(CH₃)₃; and each V² is H, and each V¹ is, independently, —N—C(═O)—R³,where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In some embodiments, each X is O or S; each R¹ is —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2; each R² is halo, —CF₃,or —C(CH₃)₃; and each V² is H, and each V¹ is —N—C(═O)—R³, where each R³is —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 3 or 4.

In some embodiments, each X is, independently, S or S(═O)₂; each R¹ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═O)—R⁴, where each nis, independently, 1 or 2, and each R⁴ is, independently,—(CH₂)_(p)—NH₂, where each p is, independently, 1 or 2; each R² is,independently, halo or —CF₃; and each V² is H, and each V¹ is,independently, —N—C(═O)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 3 or 4.

In some embodiments, each X is O or S; each R¹ is —CH₃; each R² is —CF₃;each V¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; and each R⁶ is —S—(CH₂)_(m)—NH₂ or—S—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is, independently, 1 or 2.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present disclosure also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present disclosure also provides methods of preventing or treatingcandidiasis (oral and/or disseminated) or an aspergillus infection in amammal comprising administering to the mammal in need thereof aneffective amount of a compound of Formula I:

wherein:

each X is, independently, O, S, or S(═O)₂;

each R¹ is, independently, —CH₃, —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴, where each n is,independently, 1 to 4, and each R⁴ is, independently, H, —C₁-C₃alkyl, or—(CH₂)_(p)—NH₂, where each p is, independently, 1 or 2;

each R² is, independently, H, halo, —CF₃, or —C(CH₃)₃;

each V² is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where eachn is, independently, 1 to 4; or each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; and

each R⁶ is H, —S—(CH₂)_(m)—NH₂, —S—(CH₂)_(m)—NH—C(═NH)NH₂,—O—(CH₂)_(m)—NH₂, or —O—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is,independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each X is S.

In any of the above embodiments, each R¹ is, independently, —CH₃,—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴,where each n, is independently, 1 or 2, and each R⁴ is, independently, Hor methyl; or each R¹ is, independently, —CH₃, —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴, where each n is 2and each R⁴ is H; or each R¹ is, independently, —CH₃, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2; or each R¹ is —CH₃,—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2; or eachR¹ is —CH₃ or —(CH₂)_(n)—NH₂ where each n is 2.

In any of the above embodiments, each R² is, independently, H, Br, F,Cl, —CF₃, or —C(CH₃)₃; or each R² is, independently, Br, F, Cl, —CF₃, or—C(CH₃)₃; or each R² is —CF₃.

In any of the above embodiments, each V² is H and each V¹ is,independently, —N—C(═O)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each V² is H and each V¹ is, independently,—N—C(═O)—R³, where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 or 2; or eachV² is H and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis 2; or each V² is H and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where n is 2.

In any of the above embodiments, each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachV¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis 1 or 2; or each V² is H and each V² is, independently, —S—R⁵, whereeach R⁵ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 2; or each V¹ is H and each V² is —S—R⁵, where each R⁵is —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2; or eachV¹ is H and each V² is —S—R⁵, where each R⁵ is —(CH₂)_(n)—NH₂ where eachn is 2.

In any of the above embodiments, each R⁶ is H, —S—(CH₂)_(m)—NH₂, or—S—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is, independently, 1 to 4; oreach R⁶ is H, —S—(CH₂)_(m)—NH₂, or —S—(CH₂)_(m)—NH—C(═NH)NH₂, where eachm is, independently, 1 or 2; or each R⁶ is H or—S—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is, independently, 1 or 2; oreach R⁶ is H or —S—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is 2.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, —CF₃, or—C(CH₃)₃; and each V¹ is H and each V² is, independently, —S—R⁵, whereeach R⁵ is, independently, —(CH₂)_(n)—NH₂, where each n is,independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R² is,independently, —CF₃ or —C(CH₃)₃; and each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂,where each n is, independently, 1 or 2.

In some embodiments, each X is S; each R¹ is —(CH₂)_(n)—NH₂, where eachn is 1 or 2; each R² is, independently, —CF₃ or —C(CH₃)₃; and each V¹ isH and each V² is —S—R⁵, where each R⁵ is —(CH₂)_(n)—NH₂, where each n is1 or 2.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴,where each n is, independently, 1 to 4, and each R⁴ is, independently, Hor methyl; each R² is, independently, halo, —CF₃, or —C(CH₃)₃; and eachV² is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 or 2, and eachR⁴ is, independently, H or methyl; each R² is, independently, halo; andeach V² is H, and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, —CF₃, or—C(CH₃)₃; and each V² is H, and each V¹ is, independently, —N—C(═O)—R³,where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In some embodiments, each X is O or S; each R¹ is —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2; each R² is halo, —CF₃,or —C(CH₃)₃; and each V² is H, and each V¹ is —N—C(═O)—R³, where each R³is —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 3 or 4.

In some embodiments, each X is, independently, S or S(═O)₂; each R¹ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═O)—R⁴, where each nis, independently, 1 or 2, and each R⁴ is, independently,—(CH₂)_(p)—NH₂, where each p is, independently, 1 or 2; each R² is,independently, halo or —CF₃; and each V² is H, and each V¹ is,independently, —N—C(═O)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 3 or 4.

In some embodiments, each X is O or S; each R¹ is —CH₃; each R² is —CF₃;each V¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; and each R⁶ is —S—(CH₂)_(m)—NH₂ or—S—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is, independently, 1 or 2.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides methods of killing or inhibitingthe growth of a Candida or Aspergillus species comprising contacting theCandida or Aspergillus species with an effective amount of a compound ofFormula I:

wherein:

each X is, independently, O, S, or S(═O)₂;

each R¹ is, independently, —CH₃, —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴, where each n is,independently, 1 to 4, and each R⁴ is, independently, H, —C₁-C₃alkyl, or—(CH₂)_(p)—NH₂, where each p is, independently, 1 or 2;

each R² is, independently, H, halo, —CF₃, or —C(CH₃)₃;

each V² is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where eachn is, independently, 1 to 4; or each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; and

each R⁶ is H, —S—(CH₂)_(m)—NH₂, —S—(CH₂)_(m)—NH—C(═NH)NH₂,—O—(CH₂)_(m)—NH₂, or —O—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is,independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each X is S.

In any of the above embodiments, each R¹ is, independently, —CH₃,—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴,where each n is, independently, 1 or 2, and each R⁴ is, independently, Hor methyl; or each R¹ is, independently, —CH₃, —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴, where each n is 2and each R⁴ is H; or each R¹ is, independently, —CH₃, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2; or each R¹ is —CH₃,—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2; or eachR¹ is —CH₃ or —(CH₂)_(n)—NH₂ where each n is 2.

In any of the above embodiments, each R² is, independently, H, Br, F,Cl, —CF₃, or —C(CH₃)₃; or each R² is, independently, Br, F, Cl, —CF₃, or—C(CH₃)₃; or each R² is —CF₃.

In any of the above embodiments, each V² is H and each V¹ is,independently, —N—C(═)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; or each V² is H and each V¹ is, independently,—N—C(═O)—R³, where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 or 2; or eachV² is H and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis 2; or each V² is H and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where n is 2.

In any of the above embodiments, each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4; or eachV¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis 1 or 2; or each V¹ is H and each V² is, independently, —S—R⁵, whereeach R⁵ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is 2; or each V¹ is H and each V² is —S—R⁵, where each R⁵is —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 2; or eachV¹ is H and each V² is —S—R⁵, where each R⁵ is —(CH₂)_(n)—NH₂ where eachn is 2.

In any of the above embodiments, each R⁶ is H, —S—(CH₂)_(m)—NH₂, or—S—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is, independently, 1 to 4; oreach R⁶ is H, —S—(CH₂)_(m)—NH₂, or —S—(CH₂)_(m)—NH—C(═NH)NH₂, where eachm is, independently, 1 or 2; or each R⁶ is H or—S—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is, independently, 1 or 2; oreach R⁶ is H or —S—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is 2.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, CF₃, or C(CH₃)₃;and each V¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂, where each n is, independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH₂, where each n is, independently, 1 or 2; each R² is,independently, —CF₃ or —C(CH₃)₃; and each V¹ is H and each V² is,independently, —S—R⁵, where each R⁵ is, independently, —(CH₂)_(n)—NH₂,where each n is, independently, 1 or 2.

In some embodiments, each X is S; each R¹ is —(CH₂)_(n)—NH₂, where eachn is 1 or 2; each R² is, independently, —CF₃ or —C(CH₃)₃; and each V¹ isH and each V² is —S—R⁵, where each R⁵ is —(CH₂)_(n)—NH₂, where each n is1 or 2.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, or —(CH₂)_(n)—NH—C(═O)—R⁴,where each n is, independently, 1 to 4, and each R⁴ is, independently, Hor methyl; each R² is, independently, halo, —CF₃, or —C(CH₃)₃; and eachV² is H, and each V¹ is, independently, —N—C(═O)—R³, where each R³ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4.

In some embodiments, each X is S; each R¹ is, independently,—(CH₂)_(n)—NH—C(═O)—R⁴, where each n is, independently, 1 or 2, and eachR⁴ is, independently, H or methyl; each R² is, independently, halo; andeach V² is H, and each V¹ is —N—C(═O)—R³, where each R³ is—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 4.

In some embodiments, each X is O or S; each R¹ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 1 to 4; each R² is, independently, halo, —CF₃, or—C(CH₃)₃; and each V² is H, and each V¹ is, independently, —N—C(═O)—R³,where each R³ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4.

In some embodiments, each X is O or S; each R¹ is —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2; each R² is halo, —CF₃,or —C(CH₃)₃; and each V² is H, and each V¹ is —N—C(═O)—R³, where each R³is —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 3 or 4.

In some embodiments, each X is, independently, S or S(═O)₂; each R¹ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═O)—R⁴, where each nis, independently, 1 or 2, and each R⁴ is, independently,—(CH₂)_(p)—NH₂, where each p is, independently, 1 or 2; each R² is,independently, halo or —CF₃; and each V² is H, and each V¹ is,independently, —N—C(═O)—R³, where each R³ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is,independently, 3 or 4.

In some embodiments, each X is O or S; each R¹ is —CH₃; each R² is —CF₃;each V¹ is H and each V² is, independently, —S—R⁵, where each R⁵ is,independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 4; and each R⁶ is —S—(CH₂)_(m)—NH₂ or—S—(CH₂)_(m)—NH—C(═NH)NH₂, where each m is, independently, 1 or 2.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula II:

wherein:

R₁ is H;

R₂ is —NH₂;

R¹¹ is, independently, —(CH₂)₀₋₄—R⁴ where R⁴ is chosen from hydrogen,—C₁-C₄alkyl, —C₃-C₁₂branched alkyl, —C₃-C₈cycloalkyl, phenyl optionallysubstituted with one ore more —C₁-C₄alkyl groups, —C₁-C₄alkoxy groups,or halo groups, and heteroaryl optionally substituted with one or more—C₁-C₄alkyl groups, —C₁-C₄alkoxy groups, or halo groups;

each R₉ is, independently, hydroxyethoxymethyl, methoxyethoxymethyl,polyoxyethylene, or —(CH₂)_(q)—V where q is from 1 to 5, and each V is,independently, chosen from amino, hydroxyl, —C₁-C₆alkylurea,—C₁-C₆alkylamino, —C₁-C₆dialkylamino, —NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂,amidine, guanidine, semicarbazone, imidazole, piperidine, piperazine,4-alkylpiperazine, phenyl optionally substituted with an amino,—C₁-C₆alkylamino, or —C₁-C₆dialkylamino, and lower acylamino optionallysubstituted with one or more amino, lower alkylamino, or lowerdialkylamino, where the alkylene chain is optionally substituted with anamino or hydroxyl group; and

m is 2 to at least about 30;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹¹ is, independently, —(CH₂)₀₋₄—R⁴ where R⁴is chosen from hydrogen, —C₁-C₄alkyl, —C₃-C₁₂branched alkyl, and—C₃-C₈cycloalkyl; or each R¹¹ is, independently, —(CH₂)₁₋₃—R⁴ where R⁴is chosen from hydrogen, —C₁-C₄alkyl, —C₃-C₁₂branched alkyl, and—C₃-C₈cycloalkyl; or each R¹¹ is, independently, —(CH₂)₁₋₂—R⁴ where R⁴is chosen from hydrogen or —C₁-C₄alkyl; or each R¹¹ is chosen frommethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, and benzyl.

In any of the above embodiments, each R₉ is, independently, —(CH₂)_(q)—Vwhere q is from 1 to 5, and each V is, independently, chosen from amino,hydroxyl, —C₁-C₆alkylamino, —C₁-C₆dialkylamino, —C₁-C₃alkylurea,—NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂, amidine, guanidine, semicarbazone,imidazole, piperidine, piperazine, 4-alkylpiperazine; or each R₉ is,independently, —(CH₂)_(q)—V where q is from 1 to 4, and each V is,independently, chosen from amino, hydroxyl, —C₁-C₆alkylamino,—C₁-C₆dialkylamino, —C₁-C₂alkylurea, —NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂,amidine, and guanidine; or each R₉ is, independently, —(CH₂)_(q)—V whereq is from 1 to 4, and each V is, independently, chosen from amino,—C₁-C₆alkylamino, —C₁-C₆dialkylamino, —C₁-C₂alkylurea, amidine, andguanidine; or or each R₉ is, independently, —(CH₂)_(q)—V where q is from1 to 4, and each V is, independently, chosen from amino, amidine,—C₁-C₂alkylurea, and guanidine.

In any of the above embodiments, m is 2 to at least about 20; or m is 2to at least about 10; or m is 2 to at least about 8; or m is 3 to atleast about 6; or m is 4 to at least about 5; or m is 5.

In some embodiments, R₁ is H; R₂ is —NH₂; each R¹¹ is, independently,—(CH₂)₀₋₄—R⁴ where R⁴ is chosen from hydrogen, —C₁-C₄alkyl,—C₃-C₁₂branched alkyl, and —C₃-C₈cycloalkyl; each R₉ is, independently,—(CH₂)_(q)—V where q is from 1 to 5, and each V is, independently,chosen from amino, hydroxyl, —C₁-C₆alkylamino, —C₁-C₆dialkylamino,—C₁-C₃alkylurea, —NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂, amidine, guanidine,semicarbazone, imidazole, piperidine, piperazine, 4-alkylpiperazine; andm is 2 to at least about 20.

In some embodiments, R₁ is H; R₂ is —NH₂; each R¹¹ is, independently,—(CH₂)₁₋₃—R⁴ where R⁴ is chosen from hydrogen, —C₁-C₄alkyl,—C₃-C₁₂branched alkyl, and —C₃-C₈cycloalkyl; each R₉ is, independently,—(CH₂)_(q)—V where q is from 1 to 4, and each V is, independently,chosen from amino, hydroxyl, —C₁-C₆alkylamino, —C₁-C₆dialkylamino,—NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂, amidine, —C₁-C₂alkylurea, and guanidine;and m is 2 to at least about 10.

In some embodiments, R₁ is H; R₂ is —NH₂; each R¹¹ is, independently,—(CH₂)₁₋₂—R⁴ where R⁴ is chosen from hydrogen or —C₁-C₄alkyl; each R₉is, independently, —(CH₂)_(q)—V where q is from 1 to 4, and each V is,independently, chosen from amino, —C₁-C₆alkylamino, —C₁-C₆dialkylamino,amidine, and —C₁-C₂alkylurea, guanidine; and m is 3 to at least about 6.

In some embodiments, R₁ is H; R₂ is —NH₂; each R¹¹ is chosen frommethyl, ethyl, n-propyl, iso-propyl, n-butyl iso-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, and benzyl; each R₉ is,independently, —(CH₂)_(q)—V where q is from 1 to 4, and each V isindependently, chosen from amino, amidine, —C₁-C₂alkylurea, andguanidine; and m is 4 to 5.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present disclosure also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present disclosure also provides methods of preventing or treatingcandidiasis (oral and/or disseminated) or an aspergillus infection in amammal comprising administering to the mammal in need thereof aneffective amount of a compound of Formula II:

wherein.

R₁ is H;

R₂ is —NH₂;

each R¹¹ is, independently, —(CH₂)₀₋₄—R⁴ where R⁴ is chosen fromhydrogen, —C₁-C₄alkyl, —C₃-C₁₂branched alkyl, —C₃-C₈cycloalkyl, phenyloptionally substituted with one or more —C₁-C₄alkyl groups, —C₁-C₄alkoxygroups, or halo groups, and heteroaryl optionally substituted with oneor more —C₁-C₄alkyl groups, —C₁-C₄alkoxy groups, or halo groups;

each R₉ is, independently, hydroxyethoxymethyl, methoxyethoxymethyl,polyoxyethylene, or —(CH₂)_(q)—V where q is from 1 to 5, and each V is,independently, chosen from amino, hydroxyl, —C₁-C₆alkylurea,—C₁-C₆alkylamino, —C₁-C₆dialkylamino, —NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂,amidine, guanidine, semicarbazone, imidazole, piperidine, piperazine,4-alkylpiperazine, phenyl optionally substituted with an amino,—C₁-C₆alkylamino, or —C₁-C₆dialkylamino, and lower acylamino optionallysubstituted with one or more amino, lower alkylamino, or lowerdialkylamino, where the alkylene chain is optionally substituted with anamino or hydroxyl group; and

m is 2 to at least about 30;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹¹ is, independently, —(CH₂)₀₋₄—R⁴ where R⁴is chosen from hydrogen, —C₁-C₄alkyl, —C₃-C₁₂branched alkyl, and—C₃-C₈cycloalkyl; or each R¹¹ is, independently, —(CH₂)₁₋₃—R⁴ where R⁴is chosen from hydrogen, —C₁-C₄alkyl, —C₃-C₁₂branched alkyl, and—C₃-C₈cycloalkyl; or each R¹¹ is, independently, —(CH₂)₁₋₂—R⁴ where R⁴is chosen from hydrogen or —C₁-C₄alkyl; or each R¹¹ is chosen frommethyl, ethyl, n-propyl, iso-propyl, n-butyl iso-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, and benzyl.

In any of the above embodiments, each R₉ is, independently, —(CH₂)_(q)—Vwhere q is from 1 to 5, and each V is, independently, chosen from amino,hydroxyl, —C₁-C₆alkylamino, —C₁-C₆dialkylamino, —C₁-C₃alkylurea,—NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂, amidine, guanidine, semicarbazone,imidazole, piperidine, piperazine, 4-alkylpiperazine; or each R₉ is,independently, —(CH₂)_(q)—V where q is from 1 to 4, and each V is,independently, chosen from amino, hydroxyl, —C₁-C₆alkylamino,—C₁-C₆dialkylamino, —C₁-C₂-alkylurea, —NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂,amidine, and guanidine; or each R₉ is, independently, —(CH₂)_(q)—V whereq is from 1 to 4, and each V is, independently, chosen from amino,—C₁-C₆alkylamino, —C₁-C₆dialkylamino, —C₁-C₂alkylurea, amidine, andguanidine; or or each R₉ is, independently, —(CH₂)_(q)—V where q is from1 to 4, and each V is, independently, chosen from amino, amidine,—C₁-C₂alkylurea, and guanidine.

In any of the above embodiments, m is 2 to at least about 20; or m is 2to at least about 10; or m is 2 to at least about 8; or m is 3 to atleast about 6; or m is 4 to at least about 5; or m is 5.

In some embodiments, R₁ is H; R₂ is —NH₂; each R¹¹ is, independently,—(CH₂)₀₋₄—R⁴ where R⁴ is chosen from hydrogen, —C₁-C₄alkyl,—C₃-C₁₂branched alkyl, and —C₃-C₈cycloalkyl; each R₉ is, independently,—(CH₂)_(q)—V where q is from 1 to 5, and each V is, independently,chosen from amino, hydroxyl, —C₁-C₆alkylamino, —C₁-C₆dialkylamino,—C₁-C₃alkylurea, —NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂, amidine, guanidine,semicarbazone, imidazole, piperidine, piperazine, 4-alkylpiperazine; andm is 2 to at least about 20.

In some embodiments, R₁ is H; R₂ is —NH₂; each R¹¹ is, independently,—(CH₂)₁₋₃—R⁴ where R⁴ is chosen from hydrogen, —C₁-C₄alkyl,—C₃-C₁₂branched alkyl, and —C₃-C₈cycloalkyl; each R₉ is, independently,—(CH₂)_(q)—V where q is from 1 to 4, and each V is, independently,chosen from amino, hydroxyl, —C₁-C₆alkylamino, —C₁-C₆dialkylamino,—NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂, amidine, —C₁-C₂-alkylurea, andguanidine; and m is 2 to at least about 10.

In some embodiments, R₁ is H; R₂ is —NH₂; each R¹¹ is, independently,—(CH₂)₁₋₂—R⁴ where R⁴ is chosen from hydrogen or —C₁-C₄alkyl; each R₉is, independently, —(CH₂)_(q)—V where q is from 1 to 4, and each V is,independently, chosen from amino, —C₁-C₆alkylamino, —C₁-C₆dialkylamino,amidine, and —C₁-C₂alkylurea, guanidine; and m is 3 to at least about 6.

In some embodiments, R₁ is H; R₂ is —NH₂; each R¹¹ is chosen frommethyl, ethyl, n-propyl, iso-propyl, n-butyl iso-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, and benzyl; each R₉ is,independently, —(CH₂)_(q)—V where q is from 1 to 4, and each V is,independently, chosen from amino, amidine, —C₁-C₂alkylurea, andguanidine; and m is 4 to 5.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides methods of killing or inhibitingthe growth of a Candida or Aspergillus species comprising contacting theCandida or Aspergillus species with an effective amount of a compound ofFormula II:

wherein:

R₁ is H;

R₂ is —NH₂;

each R¹¹ is, independently, —(CH₂)₀₋₄—R⁴ where R⁴ is chosen fromhydrogen, —C₁-C₄alkyl, —C₃-C₁₂branched alkyl, —C₃-C₈cycloalkyl, phenyloptionally substituted with one or more —C₁-C₄alkyl groups, —C₁-C₄alkoxygroups, or halo groups, and heteroaryl optionally substituted with oneor more —C₁-C₄alkyl groups, —C₁-C₄alkoxy groups, or halo groups;

each R₉ is, independently, hydroxyethoxymethyl, methoxyethoxymethyl,polyoxyethylene, or —(CH₂)_(q)—V where q is from 1 to 5, and each V is,independently, chosen from amino, hydroxyl, —C₁-C₆alkylurea,—C₁-C₆alkylamino, —C₁-C₆dialkylamino, —NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂,amidine, guanidine, semicarbazone, imidazole, piperidine, piperazine,4-alkylpiperazine, phenyl optionally substituted with an amino,—C₁-C₆alkylamino, or —C₁-C₆dialkylamino, and lower acylamino optionallysubstituted with one or more amino, lower alkylamino, or lowerdialkylamino, where the alkylene chain is optionally substituted with anamino or hydroxyl group; and

m is 2 to at least about 30;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹¹ is, independently, —(CH₂)₀₋₄—R⁴ where R⁴is chosen from hydrogen, —C₁-C₄alkyl, —C₃-C₁₂branched alkyl, and—C₃-C₈cycloalkyl; or each R¹¹ is, independently, —(CH₂)₁₋₃—R⁴ where R⁴is chosen from hydrogen, —C₁-C₄alkyl, —C₃-C₁₂branched alkyl, and—C₃-C₈cycloalkyl; or each R¹¹ is, independently, —(CH₂)₁₋₂—R⁴ where R⁴is chosen from hydrogen or —C₁-C₄alkyl; or each R¹¹ is chosen frommethyl, ethyl, n-propyl, iso-propyl, n-butyl iso-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, and benzyl.

In any of the above embodiments, each R₉ is, independently, —(CH₂)_(q)—Vwhere q is from 1 to 5, and each V is, independently, chosen from amino,hydroxyl, —C₁-C₆alkylamino, —C₁-C₆dialkylamino, —C₁-C₃alkylurea,—NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂, amidine, guanidine, semicarbazone,imidazole, piperidine, piperazine, 4-alkylpiperazine; or each R₉ is,independently, —(CH₂)_(q)—V where q is from 1 to 4, and each V is,independently, chosen from amino, hydroxyl, —C₁-C₆alkylamino,—C₁-C₆dialkylamino, —C₁-C₂alkylurea, —NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂,amidine, and guanidine; or each R⁹ is, independently, —(CH₂)_(q)—V whereq is from 1 to 4, and each V is, independently, chosen from amino,—C₁-C₆alkylamino, —C₁-C₆dialkylamino, —C₁-C₂alkylurea, amidine, andguanidine; or or each R₉ is, independently, —(CH₂)_(q)—V where q is from1 to 4, and each V is, independently, chosen from amino, amidine,—C₁-C₂alkylurea, and guanidine.

In any of the above embodiments, m is 2 to at least about 20; or m is 2to at least about 10; or m is 2 to at least about 8; or m is 3 to atleast about 6; or m is 4 to at least about 5; or m is or 5.

In some embodiments, R₁ is H; R₂ is —NH₂; each R¹¹ is, independently,—(CH₂)₀₋₄—R⁴ where R⁴ is chosen from hydrogen, —C₁-C₄alkyl,—C₃-C₁₂branched alkyl, and —C₃-C₈cycloalkyl; each R₉ is, independently,—(CH₂)_(q)—V where q is from 1 to 5, and each V is, independently,chosen from amino, hydroxyl, —C₁-C₆alkylamino, —C₁-C₆dialkylamino,—C₁-C₃alkylurea, —NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂, amidine, guanidine,semicarbazone, imidazole, piperidine, piperazine, 4-alkylpiperazine; andm is 2 to at least about 20.

In some embodiments, R₁ is H; R₂ is —NH₂; each R¹¹ is, independently,—(CH₂)₁₋₃—R⁴ where R⁴ is chosen from hydrogen, —C₁-C₄alkyl,—C₃-C₁₂branched alkyl, and —C₃-C₈cycloalkyl; each R₉ is, independently,—(CH₂)_(q)—V where q is from 1 to 4, and each V is, independently,chosen from amino, hydroxyl, —C₁-C₆alkylamino, —C₁-C₆dialkylamino,—NH(CH₂)₁₋₄NH₂, —N(CH₂CH₂NH₂)₂, amidine, —C₁-C₂alkylurea, and guanidine;and m is 2 to at least about 10.

In some embodiments, R₁ is H; R₂ is —NH₂; each R¹¹ is, independently,—(CH₂)₁₋₂—R⁴ where R⁴ is chosen from hydrogen or —C₁-C₄alkyl; each R₉is, independently, —(CH₂)_(q)—V where q is from 1 to 4, and each V is,independently, chosen from amino, —C₁-C₆alkylamino, —C₁-C₆dialkylamino,amidine, and —C₁-C₂alkylurea, guanidine; and m is 3 to at least about 6.

In some embodiments, R₁ is H; R₂ is —NH₂; each R¹¹ is chosen frommethyl, ethyl, n-propyl, iso-propyl, n-butyl iso-butyl, sec-butyl,tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, and benzyl; each R₉ is,independently, —(CH₂)_(q)—V where q is from 1 to 4, and each V is,independently, chosen from amino, amidine, —C₁-C₂alkylurea, andguanidine; and m is 4 to 5.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula III:

wherein:

X is —C(R⁷)C(R⁸), —C(═O), —N(R⁹), O, S, S(═O), or S(═O)₂;

R⁷, R⁸, and R⁹ are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo,—OH, —CF₃, aromatic group, —(CH₂)_(q)NH₂, or —(CH₂)_(q)NHC(═NH)NH₂,where q is 0 to 4;

R¹ and R² are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo, —OH,-haloC₁-C₈alkyl, —CN, or —CF₃;

R³ and R⁴ are, independently, H or -carbocycle(R⁵)(R⁶);

each R⁵ and each R⁶ are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy,halo, amino, —OH, —CF₃, —O—(CH₂)_(p)—NH₂, —O—(CH₂)_(p)NHC(═NH)NH₂,—S—(CH₂)_(p)—NH₂, —N((CH₂)_(p)NH₂)₂, —S—(CH₂)_(p)NHC(═NH)NH₂,—C(═O)NH(CH₂)_(p)NH₂, —(CH₂)_(p)N((CH₂)_(p)NH₂)₂, where each p is,independently, 1 to 5, aromatic group, heterocycle, or the free base orsalt form of —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 8;

provided that the compound is not Compound 116-134;

or a pharmaceutically acceptable salt thereof.

In some embodiments, X is —N(R⁹), O, S, or S(═O)₂; or X is —NH, O, S, or—N(CH₂)_(q)NH₂, where q is 2 or 3; or X is —NH, —N(CH₂)₃NH₂, or S.

In any of the above embodiments, R¹ and R² are, independently, H,—C₁-C₃alkyl, —C₁-C₃alkoxy, halo, —OH, -haloC₁-C₃alkyl, or —CN; or R¹ andR² are, independently, H, —C₁-C₃alkyl, —C₁-C₃alkoxy, halo, or —OH; or R¹and R² are, independently, H, —C₁-C₃alkyl, or halo; or R¹ and R² are H.

In any of the above embodiments, R³ and R⁴ are, independently, H or-carbocycle(R⁵)(R⁶), where R⁵ and R⁶ can be positioned anywhere on thecarbocycle. In any of the above embodiments, R³ and R⁴ are,independently,

wherein each W, Y, and Z are, independently, C or N, each A, D, and Qare, independently, —C(R¹⁰)C(R¹¹), —C(═O), —N(R¹²), O, or S, and eachR¹⁰, R¹¹, and R¹² are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy,halo, —OH, —CF₃, or aromatic group.

In any of the above embodiments, R³ and R⁴ are, independently,

wherein each W, Y, and Z are, independently, C or N; or R³ and R⁴ are,independently,

wherein each W, Y, and Z are C, or each Y and Z are C and each W is N.

In any of the above embodiments, each R⁵ is, independently, H,—C₁-C₈alkyl, —C₁-C₈alkoxy, halo, amino, —OH, —CF₃, —O—(CH₂)_(p)—NH₂,—O—(CH₂)_(p)NHC(═NH)NH₂, —S—(CH₂)_(p)—NH₂, —S—(CH₂)_(p)NHC(═NH)NH₂,—C(═O)NH(CH₂)_(p)NH₂, —N((CH₂)_(p)NH₂)₂, —(CH₂)_(p)N((CH₂)_(p)NH₂)₂,where each p is, independently, 1 to 5, or the free base of salt form of—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 8, and each R⁶ is, independently,amino, heterocycle, —O—(CH₂)_(p)—NH₂, —O—(CH₂)_(p)NHC(═NH)NH₂,—S—(CH₂)_(p)—NH₂, —S—(CH₂)_(p)NHC(═NH)NH₂, —N((CH₂)_(p)NH₂)₂,—C(═O)NH(CH₂)_(p)NH₂, —(CH₂)_(p)N((CH₂)_(p)NH₂)₂, where each p is,independently, 1 to 5, or the free base or salt form of —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 8; or each R⁵ is, independently, H, —C₁-C₃alkyl,—C₁-C₃alkoxy, halo, —OH, —CF₃, or —O—(CH₂)_(p)—NH₂, where each p is,independently, 1 to 5, and each R⁶ is, independently, heterocycle,—O—(CH₂)_(p)—NH₂, where each p is, independently, 1 to 5, or the freebase or salt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1to 8; or each R⁵ is, independently, H, —C₁-C₃alkyl, halo, —OH, or—O—(CH₂)_(p)—NH₂, where each p is, independently, 2 or 3, and each R⁶is, independently, heterocycle, —O—(CH₂)_(p)—NH₂, where each p is,independently, 2 or 3, or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is, independently, 1 to 4; or each R⁵ is, independently, H,—C₁-C₃alkyl, halo, —OH, or —O—(CH₂)₃—NH₂, and each R⁶ is, independently,6-membered heterocycle, —O—(CH₂)₃—NH₂, or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3; or each R⁵ is,independently, H, halo, or —O—(CH₂)₃—NH₂, and each R⁶ is piperazinyl,—O—(CH₂)₃—NH₂, or the free base or salt form of —(CH₂)_(n)—NH₂ whereeach n is, independently, 1 to 3; or each R⁵ is —O—(CH₂)₃—NH₂ orpiperazinyl, and each R⁶ is, independently, H, —C₁-C₃alkyl,—C₁-C₃alkoxy, halo, —OH, —CF₃, or —O—(CH₂)₃—NH₂, or each R⁵ ispiperazinyl or —O—(CH₂)₃—NH₂; and each R⁶ is H, —C₁-C₃alkyl, halo, —OH,—CF₃, or —O—(CH₂)₃—NH₂.

In some embodiments, X is —NH, O, S, S(═O)₂, or —N(CH₂)₂₋₃NH₂; R¹ and R²are H; R³ and R⁴ are, independently,

wherein: each W, Y, and Z are, independently, C or N; each R⁵ and eachR⁶ are, independently, H, heterocycle, —O—(CH₂)_(p)—NH₂, where each pis, independently, 1 to 3, or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3.

In some embodiments, X is —NH, O, S, or —N(CH₂)₂₋₃NH₂; R¹ and R² are H;R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;each R⁵ is, independently, H, amino, halo, or —O—(CH₂)_(p)—NH₂,—C(═O)NH(CH₂)_(p)NH₂, —N((CH₂)_(p)NH₂)₂, —(CH₂)_(p)N((CH₂)_(p)NH₂)₂,where each p is, independently, 2 or 3, and each R⁶ is piperazinyl,amino, —C(═O)NH(CH₂)_(p)NH₂, —N((CH₂)_(p)NH₂)₂,—(CH₂)_(p)N((CH₂)_(p)NH₂)₂, —O—(CH₂)_(p)—NH₂, where each p is,independently, 2 or 3, or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is, independently, 1 to 3; or each R⁵ is piperazinyl or—O—(CH₂)₃—NH₂, and each R⁶ is, independently, H, —C₁-C₃alkyl,—C₁-C₃alkoxy, halo, —OH, —CF₃, or —O—(CH₂)₃—NH₂.

In some embodiments, X is —NH, O, S, or —N(CH₂)₂₋₃NH₂; R¹ and R² are H;R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;each R⁵ is H or —O—(CH₂)₃—NH₂, and each R⁶ is piperazinyl,—O—(CH₂)₃—NH₂, or the free base or salt form of —(CH₂)_(n)—NH₂, whereeach n is, independently, 1 to 3; or each R⁵ is piperazinyl or—O—(CH₂)₃—NH₂; and each R⁶ is H or —O—(CH₂)₃—NH₂.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present disclosure also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present disclosure also provides methods of preventing or treatingcandidiasis (oral and/or disseminated) or an aspergillus infection in amammal comprising administering to the mammal in need thereof aneffective amount of a compound of Formula III:

wherein:

X is —C(R⁷)C(R⁸), —C(═O), N(R⁹), O, S, S(═O), or S(═O)₂;

R⁷, R⁸, and R⁹ are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo,—OH, —CF₃, aromatic group, —(CH₂)_(q)NH₂, or —(CH₂)_(q)NHC(═NH)NH₂,where q is 0 to 4;

R¹ and R² are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo, —OH,-haloC₁-C₈alkyl, —CN, or —CF₃;

R³ and R⁴ are, independently, H or -carbocycle (R⁵)(R⁶);

each R⁵ and R⁶ are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo,amino, —OH, —CF₃, —O—(CH₂)_(p)—NH₂, —O—(CH₂)_(p)NHC(═NH)NH₂,—S—(CH₂)_(p)—NH₂, —N((CH₂)_(p)NH₂)₂, —S—(CH₂)_(p)NHC(═NH)NH₂,—C(═O)NH(CH₂)_(p)NH₂, —(CH₂)_(p)N((CH₂)_(p)NH₂)₂, where each p is,independently, 1 to 5, aromatic group, heterocycle, or the free base orsalt form of —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 8;

or a pharmaceutically acceptable salt thereof.

In some embodiments, X is —N(R⁹), O, S, or S(═O)₂; or X is —NH, O, S, or—N(CH₂)_(q)NH₂, where q is 2 or 3; or X is —NH, —N(CH₂)₃NH₂, or S.

In any of the above embodiments, R¹ and R² are, independently, H,—C₁-C₃alkyl, —C₁-C₃alkoxy, halo, —OH, -haloC₁-C₃alkyl, or —CN; or R¹ andR² are, independently, H, —C₁-C₃alkyl, —C₁-C₃alkoxy, halo, or —OH; or R¹and R² are, independently, H, —C₁-C₃alkyl, or halo; or R¹ and R² are H.

In any of the above embodiments, R³ and R⁴ are, independently, H or-carbocycle(R⁵)R⁶), where R⁵ and R⁶ can be positioned anywhere on thecarbocycle. In any of the above embodiments, R³ and R⁴ are,independently,

wherein each W, Y, and Z are, independently, C or N, each A, D, and Qare, independently, —C(R¹⁰)C(R¹¹), —C(═O), —N(R¹²), O, or S, and eachR¹⁰, R¹¹, and R¹² are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy,halo, —OH, —CF₃, or aromatic group.

In any of the above embodiments, R³ and R⁴ are, independently,

wherein each W, Y, and Z are, independently, C or N; or R³ and R⁴ are,independently,

wherein each W, Y, and Z are C, or each Y and Z are C and each W is N.

In any of the above embodiments, each R⁵ is, independently, H,—C₁-C₈alkyl, —C₁-C₈alkoxy, halo, amino, —OH, —CF₃, —O—(CH₂)_(p)—NH₂,—O—(CH₂)_(p)NHC(═NH)NH₂, —S—(CH₂)_(p)—NH₂, —S—(CH₂)_(p)NHC(═NH)NH₂,—C(═O)NH(CH₂)_(p)NH₂, —N((CH₂)_(p)NH₂)₂, —(CH₂)_(p)N((CH₂)_(p)NH₂)₂,where each p is, independently, 1 to 5, or the free base or salt form of—(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 8, and each R⁶ is, independently,heterocycle, amino, —O—(CH₂)_(p)—NH₂, —O—(CH₂)_(p)NHC(═NH)NH₂,—S—(CH₂)_(p)—NH₂, —S—(CH₂)_(p)NHC(═NH)NH₂, —N((CH₂)_(p)NH₂)₂,—C(═O)NH(CH₂)_(p)NH₂, —(CH₂)_(p)N((CH₂)_(p)NH₂)₂, where each p is,independently, 1 to 5, or the free base or salt form of —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 8; or each R⁵ is, independently, H, —C₁-C₃alkyl,—C₁-C₃alkoxy, halo, —OH, —CF₃, or —O—(CH₂)_(p)—NH₂, where each p is,independently, 1 to 5, and each R⁶ is, independently, heterocycle,—O—(CH₂)_(p)—NH₂, where each p is, independently, 1 to 5, or the freebase or salt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1to 8; or each R⁵ is, independently, H, —C₁-C₃alkyl, halo, —OH, or—O—(CH₂)_(p)—NH₂, where each p is, independently, 2 or 3, and each R⁶is, independently, heterocycle, —O—(CH₂)_(p)—NH₂, where each p is,independently, 2 or 3, or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is, independently, 1 to 4; or each R⁵ is, independently, H,—C₁-C₃alkyl, halo, —OH, or —O—(CH₂)₃—NH₂, and each R⁶ is, independently,6-membered heterocycle, —O—(CH₂)₃—NH₂, or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3; or each R⁵ is,independently, H, halo, or —O—(CH₂)₃—NH₂, and each R⁶ is piperazinyl,—O—(CH₂)₃—NH₂, or the free base or salt form of —(CH₂)_(n)—NH₂ whereeach n is, independently, 1 to 3; or each R⁵ is —O—(CH₂)₃—NH₂ orpiperazinyl, and each R⁶ is, independently, H, —C₁-C₃alkyl,—C₁-C₃alkoxy, halo, —OH, —CF₃, or —O—(CH₂)₃—NH₂, or each R⁵ ispiperazinyl or —O—(CH₂)₃—NH₂; and each R⁶ is H, —C₁-C₃alkyl, halo, —OH,—CF₃, or —O—(CH₂)₃—NH₂.

In some embodiments, X is —NH, O, S, S(═O)₂, or —N(CH₂)₂₋₃NH₂; R¹ and R²are H; R³ and R⁴ are, independently,

wherein: each W, Y, and Z are, independently, C or N; each R⁵ and eachR⁶ are, independently, H, heterocycle, —O—(CH₂)_(p)—NH₂, where each pis, independently, 1 to 3, or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3.

In some embodiments, X is —NH, O, S, or —N(CH₂)₂₋₃NH₂; R¹ and R² are H;R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;each R⁵ is, independently, H, halo, amino, or —O—(CH₂)_(p)—NH₂,—C(═O)NH(CH₂)_(p)NH₂, —N((CH₂)_(p)NH₂)₂, —(CH₂)_(p)N((CH₂)_(p)NH₂)₂,where each p is, independently, 2 or 3, and each R⁶ is piperazinyl,amino, —C(═O)NH(CH₂)_(p)NH₂, —N((CH₂)_(p)NH₂)₂,—(CH₂)_(p)N((CH₂)_(p)NH₂)₂, —O—(CH₂)_(p)—NH₂, where each p is,independently, 2 or 3, or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is, independently, 1 to 3; or each R⁵ is piperazinyl or—O—(CH₂)₃—NH₂, and each R⁶ is, independently, H, —C₁-C₃alkyl,—C₁-C₃alkoxy, halo, —OH, —CF₃, or —O—(CH₂)₃—NH₂.

In some embodiments, X is —NH, O, S, or —N(CH₂)₂₋₃NH₂; R¹ and R² are H;R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;each R⁵ is H or —O—(CH₂)₃—NH₂, and each R⁶ is piperazinyl,—O—(CH₂)₃—NH₂, or the free base or salt form of —(CH₂)_(n)—NH₂, whereeach n is, independently, 1 to 3; or each R⁵ is piperazinyl or—O—(CH₂)₃—NH₂; and each R⁶ is H or —O—(CH₂)₃—NH₂.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides methods of killing or inhibitingthe growth of a Candida or Aspergillus species comprising contacting theCandida or Aspergillus species with an effective amount of a compound ofFormula III:

wherein:

X is —C(R⁷)C(R⁸), —C(═O), —N(R⁹), O, S, S(═O), or S(═O)₂;

R⁷, R⁸, and R⁹ are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo,—OH, —CF₃, aromatic group, —(CH₂)_(q)NH₂, or —(CH₂)_(q)NHC(═NH)NH₂,where q is 0 to 4;

R¹ and R² are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo, —OH,-haloC₁-C₈alkyl, —CN, or —CF₃;

R³ and R⁴ are, independently, H or -carbocycle(R⁵)(R⁶);

each R⁵ and each R⁶ are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy,halo, amino, —OH, —CF₃, —O—(CH₂)_(p)—NH₂, —O—(CH₂)_(p)NHC(═NH)NH₂,—S—(CH₂)_(p)—NH₂, —N((CH₂)_(p)NH₂)₂, —S—(CH₂)_(p)NHC(═NH)NH₂,—C(═O)NH(CH₂)_(p)NH₂, —(CH₂)_(p)N((CH₂)_(p)NH₂)₂, where each p is,independently, 1 to 5, aromatic group, heterocycle, or the free base orsalt form of —(CH₂)_(n)—NH₂, —(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 8;

or a pharmaceutically acceptable salt thereof.

In some embodiments, X is —N(R⁹), O, S, or S(═O)₂; or X is —NH, O, S, or—N(CH₂)_(q)NH₂, where q is 2 or 3; or X is —NH, —N(CH₂)₃NH₂, or S.

In any of the above embodiments, R¹ and R² are, independently, H,—C₁-C₃alkyl, —C₁-C₃alkoxy, halo, —OH, -haloC₁-C₃alkyl, or —CN; or R¹ andR² are, independently, H, —C₁-C₃alkyl, —C₁-C₃alkoxy, halo, or —OH; or R¹and R² are, independently, H, —C₁-C₃alkyl, or halo; or R¹ and R² are H.

In any of the above embodiments, R³ and R⁴ are, independently, H or-carbocycle(R⁵)(R⁶), where R⁵ and R⁶ can be positioned anywhere on thecarbocycle. In any of the above embodiments, R³ and R⁴ are,independently,

wherein each W, Y, and Z are, independently, C or N, each A, D, and Qare, independently, —C(R¹⁰)C(R¹¹), —C(═O), —N(R¹²), O, or S, and eachR¹⁰, R¹¹, and R¹² are, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy,halo, —OH, —CF₃, or aromatic group.

In any of the above embodiments, R³ and R⁴ are, independently,

wherein each W, Y, and Z are, independently, C or N; or R³ and R⁴ are,independently,

wherein each W, Y, and Z are C, or each Y and Z are C and each W is N.

In any of the above embodiments, each R⁵ is, independently, H,—C₁-C₈alkyl, —C₁-C₈alkoxy, halo, amino, —OH, —CF₃, —O—(CH₂)_(p)—NH₂,—O—(CH₂)_(p)NHC(═NH)NH₂, —N((CH₂)_(p)NH₂)₂, —S—(CH₂)_(p)—NH₂,—S—(CH₂)_(p)NHC(═NH)NH₂, —C(═O)NH(CH₂)_(p)NH₂,—(CH₂)_(p)N((CH₂)_(p)NH₂)₂, where each p is, independently, 1 to 5, orthe free base or salt form of —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 8, and each R⁶ is, independently, heterocycle,amino, —O—(CH₂)_(p)—NH₂, —O—(CH₂)_(p)NHC(═NH)NH₂, —S—(CH₂)_(p)—NH₂,—S—(CH₂)_(p)NHC(═NH)NH₂, —N((CH₂)_(p)NH₂)₂, —C(═O)NH(CH₂)_(p)NH₂,—(CH₂)_(p)N((CH₂)_(p)NH₂)₂, where each p is, independently, 1 to 5, orthe free base or salt form of —(CH₂)_(n)—NH₂,—(CH₂)_(n)—NH—(CH₂)_(n)—NH₂, or —(CH₂)_(n)—NH—C(═NH)NH₂, where each nis, independently, 1 to 8; or each R⁵ is, independently, H, —C₁-C₃alkyl,—C₁-C₃alkoxy, halo, —OH, —CF₃, or —O—(CH₂)_(p)—NH₂, where each p is,independently, 1 to 5, and each R⁶ is, independently, heterocycle,—O—(CH₂)_(p)—NH₂, where each p is, independently, 1 to 5, or the freebase or salt form of —(CH₂)_(n)—NH₂, where each n is, independently, 1to 8; or each R⁵ is, independently, H, —C₁-C₃alkyl, halo, —OH, or—O—(CH₂)_(p)—NH₂, where each p is, independently, 2 or 3, and each R⁶is, independently, heterocycle, —O—(CH₂)_(p)—NH₂, where each p is,independently, 2 or 3, or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is, independently, 1 to 4; or each R⁵ is, independently, H,—C₁-C₃alkyl, halo, —OH, or —O—(CH₂)₃—NH₂, and each R⁶ is, independently,6-membered heterocycle, —O—(CH₂)₃—NH₂, or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3; or each R⁵ is,independently, H, halo, or —O—(CH₂)₃—NH₂, and each R⁶ is piperazinyl,—O—(CH₂)₃—NH₂, or the free base or salt form of —(CH₂)_(n)—NH₂ whereeach n is, independently, 1 to 3; or each R⁵ is —O—(CH₂)₃—NH₂ orpiperazinyl, and each R⁶ is, independently, H, —C₁-C₃alkyl,—C₁-C₃alkoxy, halo, —OH, —CF₃, or —O—(CH₂)₃—NH₂, or each R⁵ ispiperazinyl or —O—(CH₂)₃—NH₂; and each R⁶ is H, —C₁-C₃alkyl, halo, —OH,—CF₃, or —O—(CH₂)₃—NH₂.

In some embodiments, X is —NH, O, S, S(═O)₂, or —N(CH₂)₂₋₃NH₂; R¹ and R²are H; R³ and R⁴ are, independently,

wherein: each W, Y, and Z are, independently, C or N; each R⁵ and eachR⁶ are, independently, H, heterocycle, —O—(CH₂)_(p)—NH₂, where each pis, independently, 1 to 3, or the free base or salt form of—(CH₂)_(n)—NH₂, where each n is, independently, 1 to 3.

In some embodiments, X is —NH, O, S, or —N(CH₂)₂₋₃NH₂; R¹ and R² are H;R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;each R⁵ is, independently, H, halo, or amino, —O—(CH₂)_(p)—NH₂,—C(═O)NH(CH₂)_(p)NH₂, —N((CH₂)_(p)NH₂)₂, —(CH₂)_(p)N((CH₂)_(p)NH₂)₂,where each p is, independently, 2 or 3, and each R⁶ is piperazinyl,amino, —C(═O)NH(CH₂)_(p)NH₂, —N((CH₂)_(p)NH₂)₂,—(CH₂)_(p)N((CH₂)_(p)NH₂)₂, —O—(CH₂)_(p)—NH₂, where each p is,independently, 2 or 3, or the free base or salt form of —(CH₂)_(n)—NH₂,where each n is, independently, 1 to 3; or each R⁵ is piperazinyl or—O—(CH₂)₃—NH₂, and each R⁶ is independently, H, —C₁-C₃alkyl,—C₁-C₃alkoxy, halo, —OH, —CF₃, or —O—(CH₂)₃—NH₂.

In some embodiments, X is —NH, O, S, or —N(CH₂)₂₋₃NH₂; R¹ and R² are H;R³ and R⁴ are

where each Z and Y are C, and each W is N; or each W, Y, and Z are C;each R⁵ is H or —O—(CH₂)₃—NH₂, and each R⁶ is piperazinyl,—O—(CH₂)₃—NH₂, or the free base or salt form of —(CH₂)_(n)—NH₂, whereeach n is, independently, 1 to 3; or each R⁵ is piperazinyl or—O—(CH₂)₃—NH₂; and each R⁶ is H or —O—(CH₂)₃—NH₂.

In some embodiments, the compound is chosen from:

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula IV

wherein:

R¹ and R² are, independently, —C(═NH)NH₂, —(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═NH)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ and R² are, independently, —C(═NH)NH₂,—(CH₂)_(n)NH₂, or —(CH₂)_(n)NC(═NH)NH₂, where n is 2 or 3.

In some embodiments, R¹ and R² are, independently, —C(═NH)NH₂ or—(CH₂)_(n)NH₂, where n is 2 or 3.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present disclosure also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present disclosure also provides methods of preventing or treatingcandidiasis (oral and/or disseminated) or an aspergillus infection in amammal comprising administering to the mammal in need thereof aneffective amount of a compound of Formula IV:

wherein:

R¹ and R² are, independently, —C(═NH)NH₂, —(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═NH)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ and R² are, independently, —C(═NH)NH₂,—(CH₂)_(n)NH₂, or —(CH₂)_(n)NC(═NH)NH₂, where n is 2 or 3.

In some embodiments, R¹ and R² are, independently, —C(═NH)NH₂ or—(CH₂)_(n)NH₂, where n is 2 or 3.

In some embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides methods of killing or inhibitingthe growth of a Candida or Aspergillus species comprising contacting theCandida or Aspergillus species with an effective amount of a compound ofFormula IV:

wherein:

R¹ and R² are, independently, —C(═NH)NH₂, —(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═NH)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ and R² are, independently, —C(═NH)NH₂,—(CH₂)_(n)NH₂, or —(CH₂)_(n)NC(═NH)NH₂, where n is 2 or 3.

In some embodiments, R¹ and R² are, independently, —C(═NH)NH₂ or—(CH₂)_(n)NH₂, where n is 2 or 3.

In some embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula V:

wherein:

R¹ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R² is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂,—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R¹ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3,or 4; or R¹ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, wheren is 2, 3, or 4; or R¹ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is2, 3, or 4; or R¹ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R² is —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R²is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R² is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R² is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R² is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R³ is —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R³is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R⁴ is —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁴is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁴ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁴ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁴ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R⁵ is —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁵is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁵ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁵ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁵ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R⁶ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁶ is H, —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁶ is H or—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁶ is H or —O—(CH₂)_(n)NH₂,where n is 3 or 4.

In any of the above embodiments, R⁷ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁷ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁷ is H, —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁷ is H or—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁷ is H or —O—(CH₂)_(n)NH₂,where n is 3 or 4.

In some embodiments:

R¹ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R² is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁴ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁵ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4.

In some embodiments:

R¹ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R² is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4.

In some embodiments:

R¹ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R² is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R⁴ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R⁵ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is2, 3, or 4.

In some embodiments:

R¹ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R² is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R³ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4; and

R⁷ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In some embodiments:

R¹ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R² is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R³ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H or —O—(CH₂)_(n)NH₂, where n is 3 or 4; and

R⁷ is H or —O—(CH₂)_(n)NH₂, where n is 3 or 4.

In some embodiments, the compound is

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present disclosure also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present disclosure also provides methods of preventing or treatingcandidiasis (oral and/or disseminated) or an aspergillus infection in amammal comprising administering to the mammal in need thereof aneffective amount of a compound of Formula V:

wherein:

R¹ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R² is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂,—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R¹ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3,or 4; or R¹ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, wheren is 2, 3, or 4; or R¹ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is2, 3, or 4; or R¹ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R² is —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R²is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R² is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R² is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R² is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R³ is —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R³is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R⁴ is —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁴is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁴ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁴ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁴ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R⁵ is —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁵is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁵ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁵ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁵ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R⁶ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁶ is H, —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁶ is H or—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁶ is H or —O—(CH₂)_(n)NH₂,where n is 3 or 4.

In any of the above embodiments, R⁷ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁷ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁷ is H, —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁷ is H or—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁷ is H or —O—(CH₂)_(n)NH₂,where n is 3 or 4.

In some embodiments:

R¹ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R² is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁴ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁵ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4.

In some embodiments:

R¹ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R² is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4.

In some embodiments:

R¹ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R² is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R⁴ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R⁵ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is2, 3, or 4.

In some embodiments:

R¹ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R² is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R³ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4; and

R⁷ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In some embodiments:

R¹ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R² is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R³ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H or —O—(CH₂)_(n)NH₂, where n is 3 or 4; and

R⁷ is H or —O—(CH₂)_(n)NH₂, where n is 3 or 4.

In some embodiments, the compound is

The present disclosure also provides methods of killing or inhibitingthe growth of a Candida or Aspergillus species comprising contacting theCandida or Aspergillus species with an effective amount of a compound ofFormula V:

wherein:

R¹ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R² is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂,—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R¹ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3,or 4; or R¹ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, wheren is 2, 3, or 4; or R¹ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is2, 3, or 4; or R¹ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R² is —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R²is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R² is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R² is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R² is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R³ is —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R³is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R⁴ is —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁴is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁴ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁴ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁴ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R⁵ is —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁵is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁵ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁵ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁵ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R⁶ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2,3, or 4; or R⁶ is H, —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁶ is H or—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁶ is H or —O—(CH₂)_(n)NH₂,where n is 3 or 4.

In any of the above embodiments, R⁷ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁷ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁷ is H, —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁷ is H or—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁷ is H or —O—(CH₂)_(n)NH₂,where n is 3 or 4.

In some embodiments:

R¹ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R² is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁴ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁵ is —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4.

In some embodiments:

R¹ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R² is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4.

In some embodiments:

R¹ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R² is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R³ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R⁴ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R⁵ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is2, 3, or 4; and

R⁷ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is2, 3, or 4.

In some embodiments:

R¹ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R² is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R³ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4; and

R⁷ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In some embodiments:

R¹ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R² is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R³ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H or —O—(CH₂)_(n)NH₂, where n is 3 or 4; and

R⁷ is H or —O—(CH₂)_(n)NH₂, where n is 3 or 4.

In some embodiments, the compound is

The present disclosure also provides compounds of Formula VI:

wherein:

R¹ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R² is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R³ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)_(n)NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4; and

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)_(n)NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, R² is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂,—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R² is H,—NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or —(CH₂)_(n)NC(═N)NH₂,where n is 2, 3, or 4; or R² is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂,where n is 2, 3, or 4; or R² is H or —(CH₂)_(n)NH₂, where n is 2, 3, or4; or R² is H.

In any of the above embodiments, R⁴ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁴ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁴ is H, —(CH₂)_(n)NH₂,or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁴ is H or —(CH₂)_(n)NH₂,where n is 2, 3, or 4; or R⁴ is H.

In any of the above embodiments, R⁵ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁵ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁵ is H, —(CH₂)_(n)NH₂,or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁵ is H or —(CH₂)_(n)NH₂,where n is 2, 3, or 4; or R⁵ is H.

In any of the above embodiments, R⁶ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂,—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁶ is H, —(CH₂)_(n)NH₂,or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁶ is H or —(CH₂)_(n)NH₂,where n is 2, 3, or 4; or R⁶ is H.

In any of the above embodiments, R¹ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR¹ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R¹ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R¹ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R¹ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R³ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR³ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R³ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In some embodiments:

R² is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n))NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R¹ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4; and

R³ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4.

In some embodiments:

R² is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R¹ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R³ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

In some embodiments:

R² is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R¹ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4; and

R³ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4.

In some embodiments:

R² is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R¹ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; and

R³ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In some embodiments:

R², R⁴, R⁵, and R⁶ are H;

R¹ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; and

R³ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In some embodiments, the compound is

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present disclosure also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present disclosure also provides methods of preventing or treatingcandidiasis (oral, and/or disseminated) or an aspergillus infection in amammal comprising administering to the mammal in need thereof aneffective amount of a compound of Formula VI:

wherein:

R¹ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R² is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R³ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂,—C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, R² is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂,—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R² is H,—NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or —(CH₂)_(n)NC(═N)NH₂,where n is 2, 3, or 4; or R² is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂,where n is 2, 3, or 4; or R² is H or —(CH₂)_(n)NH₂, where n is 2, 3, or4; or R² is H.

In any of the above embodiments, R⁴ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁴ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁴ is H, —(CH₂)_(n)NH₂,or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁴ is H or —(CH₂)_(n)NH₂,where n is 2, 3, or 4; or R⁴ is H.

In any of the above embodiments, R⁵ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁵ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁵ is H, —(CH₂)_(n)NH₂,or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁵ is H or —(CH₂)_(n)NH₂,where n is 2, 3, or 4; or R⁵ is H.

In any of the above embodiments, R⁶ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁶ is H, —(CH₂)_(n)NH₂,or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁶ is H or —(CH₂)_(n)NH₂,where n is 2, 3, or 4; or R⁶ is H.

In any of the above embodiments, R¹ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR¹ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R¹ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R¹ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R¹ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R³ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR³ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R³ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In some embodiments:

R² is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R³ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R¹ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4; and

R³ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4.

In some embodiments:

R² is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R¹ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; and

R³ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

In some embodiments:

R² is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R¹ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4; and

R³ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4.

In some embodiments:

R² is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R¹ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; and

R³ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In some embodiments:

R², R⁴, R⁵, and R⁶ is H;

R¹ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; and

R³ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In some embodiments, the compound is

The present disclosure also provides methods of killing or inhibitingthe growth of a Candida or Aspergillus species comprising contacting theCandida or Aspergillus species with an effective amount of a compound ofFormula VI:

wherein:

R¹ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R² is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R³ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4; and

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —O—(CH₂)_(n)NC(═N)NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂—NC(═N)NH₂, where n is 2, 3, or 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, R² is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂,—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R² is H,—NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or —(CH₂)_(n)NC(═N)NH₂,where n is 2, 3, or 4; or R² is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂,where n is 2, 3, or 4; or R² is H or —(CH₂)_(n)NH₂, where n is 2, 3, or4; or R² is H.

In any of the above embodiments, R⁴ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁴ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁴ is H, —(CH₂)_(n)NH₂,or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁴ is H or —(CH₂)_(n)NH₂,where n is 2, 3, or 4; or R⁴ is H.

In any of the above embodiments, R⁵ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁵ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁵ is H, —(CH₂)_(n)NH₂,or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁵ is H or —(CH₂)_(n)NH₂,where n is 2, 3, or 4; or R⁵ is H.

In any of the above embodiments, R⁶ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R⁶ is H, —(CH₂)_(n)NH₂,or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R⁶ is H or—(CH₂)_(n)NH₂,where n is 2, 3, or 4; or R⁶ is H.

In any of the above embodiments, R¹ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR¹ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R¹ is —NH(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R¹ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R¹ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In any of the above embodiments, R³ is H, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; orR³ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; or R³ is —NH(CH₂)_(n)NH2,—(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is—(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; or R³ is—O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In some embodiments:

R² is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4;

R¹ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4; and

R³ is H, —NH(CH₂)_(n)NH₂, —NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, or —O—(CH₂)_(n)NC(═N)NH₂, where nis 2, 3, or 4.

In some embodiments:

R² is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R⁴ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R⁵ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R⁶ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

R¹ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4; and

R³ is H, —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═N)NH₂, where n is 2, 3, or 4;

In some embodiments:

R² is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R¹ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4; and

R³ is —NH(CH₂)_(n)NH₂, —(CH₂)_(n)NH₂, or —O—(CH₂)_(n)NH₂, where n is 2,3, or 4.

In some embodiments:

R² is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁴ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁵ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R⁶ is H or —(CH₂)_(n)NH₂, where n is 2, 3, or 4;

R¹ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; and

R³ is —(CH₂)_(n)NH₂ or —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In some embodiments:

R², R⁴, R⁵, and R⁶ is H;

R¹ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4; and

R³ is —O—(CH₂)_(n)NH₂, where n is 2, 3, or 4.

In some embodiments, the compound is

The present disclosure also provides compounds of Formula VII:

wherein:

each R¹ is, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo, —OH,—CF₃, or —CN;

each R² is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹ is, independently, —C₁-C₈alkyl, halo, —OH,—CF₃, or —CN. In some embodiments, each R¹ is, independently,—C₁-C₃alkyl, halo, —CF₃, or —CN. In some embodiments, each R¹ is methylor halo. In some embodiments, each R¹ is Br, F, or Cl.

In any of the above embodiments, each R² is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4. In someembodiments, each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.In some embodiments, each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is1 or 2.

In some embodiments, each R¹ is, independently, —C₁-C₈alkyl, halo, —OH,—CF₃, or —CN; and each R² is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4.

In some embodiments, each R¹ is, independently, —C₁-C₃alkyl, halo, —CF₃,or —CN; and each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.

In some embodiments, each R¹ is methyl or halo; and each R² is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2.

In some embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present disclosure also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present disclosure also provides methods of preventing or treatingcandidiasis (oral and/or disseminated) or an aspergillus infection. In amammal comprising administering to the mammal in need thereof aneffective amount of a compound of Formula VII:

wherein:

each R¹ is, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo, —OH,—CF₃, or —CN;

each R² is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹ is, independently, —C₁-C₈alkyl, halo, —OH,—CF₃, or —CN. In some embodiments, each R¹ is, independently,—C₁-C₃alkyl, halo, —CF₃, or —CN. In some embodiments, each R¹ is methylor halo. In some embodiments, each R¹ is Br, F, or Cl.

In any of the above embodiments, each R² is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4. In someembodiments, each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.In some embodiments, each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is1 or 2.

In some embodiments, each R¹ is, independently, —C₁-C₈alkyl, halo, —OH,—CF₃, or —CN; and each R² is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4.

In some embodiments, each R¹ is, independently, —C₁-C₃alkyl, halo, —CF₃,or —CN; and each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.

In some embodiments, each R¹ is methyl or halo; and each R² is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2.

In some embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides methods of killing or inhibitingthe growth of a Candida or Aspergillus species comprising contacting theCandida or Aspergillus species with an effective amount of a compound ofFormula VII:

wherein:

each R¹ is, independently, H, —C₁-C₈alkyl, —C₁-C₈alkoxy, halo, —OH,—CF₃, or —CN;

each R² is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹ is, independently, —C₁-C₈alkyl, halo, —OH,—CF₃, or —CN. In some embodiments, each R¹ is, independently,—C₁-C₃alkyl, halo, —CF₃, or —CN. In some embodiments, each R¹ is methylor halo. In some embodiments, each R¹ is Br, F, or Cl.

In any of the above embodiments, each R² is, independently,—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is, independently, 1 to 4. In someembodiments, each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.In some embodiments, each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is1 or 2.

In some embodiments, each R¹ is, independently, —C₁-C₈alkyl, halo, —OH,—CF₃, or —CN; and each R² is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂,where each n is, independently, 1 to 4.

In some embodiments, each R¹ is, independently, —C₁-C₃alkyl, halo, —CF₃,or —CN; and each R² is —(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 to 4.

In some embodiments, each R¹ is methyl or halo; and each R² is—(CH₂)_(n)—NH—C(═NH)NH₂, where each n is 1 or 2.

In some embodiments, the compound is:

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula VIII:

wherein:

R¹ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R² is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R³ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂,—CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁴ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁵ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁶ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁷ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁸ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4; and

R⁹ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is halo, —CF₃, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—C≡C—CH₂NH₂, —(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, or—C≡C—CH₂NC(═N)NH₂. In some embodiments, R¹ is halo, —CF₃, —(CH₂)₂NH₂,—(CH₂)₃NH₂, —O—(CH₂)₃NH₂, —(CH₂)₃NC(═N)NH₂, —(CH₂)₂NC(═N)NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—CH₂NH₂, or —C≡C—CH₂NC(═N)NH₂.

In any of the above embodiments, R² is halo, —CF₃, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂,—CH═CH—CH₂NH₂, —C≡C—CH₂NH₂, or —C≡C—CH₂NC(═N)NH₂. In some embodiments,R² is halo, —CF₃, —(CH₂)₂NH₂, —(CH₂)₃NH₂, —O—(CH₂)₃NH₂,—(CH₂)₃NC(═N)NH₂, —(CH₂)₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, or —C≡C—CH₂NC(═N)NH₂.

In any of the above embodiments, R³ is H, —CF₃, —O—(CH₂)_(n)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂. In some embodiments, R³ is H, —CF₃, —O—(CH₂)₃NH₂,or —O—(CH₂)₃NC(═N)NH₂.

In any of the above embodiments, R⁴ is H, halo, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂,—CH═CH—CH₂NH₂, —C≡C—(CH₂)_(n)NH₂, or —C≡C—(CH₂)_(n)NC(═N)NH₂. In someembodiments, R⁴ is H, halo, —O—(CH₂)₃NH₂, —(CH₂)₂NH₂, —(CH₂)₂NC(═N)NH₂,—C≡C—CH₂NH₂, —CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂,—C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂NC(═N)NH₂.

In any of the above embodiments, R⁵ is H, halo, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂,—C≡C—(CH₂)_(n)NH₂, or —C≡C—(CH₂)_(n)NC(═N)NH₂. In some embodiments, R⁵is H, halo, —O—(CH₂)₃NH₂, —(CH₂)₂NH₂, —(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂NC(═N)NH₂.

In any of the above embodiments, R⁶ is H, —(CH₂)_(n)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂. In some embodiments, R⁶ is H, —(CH₂)₃NH₂, or—O—(CH₂)₃NC(═N)NH₂.

In any of the above embodiments, R⁷ is H, —(CH₂)_(n)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂. In some embodiments, R⁷ is H, —(CH₂)₃NH₂, or—O—(CH₂)₃NC(═N)NH₂.

In any of the above embodiments, R⁸ is H or halo.

In any of the above embodiments, R⁹ is H or halo.

In some embodiments, R¹ is halo, —CF₃, —(CH₂)₂NH₂, —(CH₂)₃NH₂,—O—(CH₂)₃NH₂, —(CH₂)₃NC(═N)NH₂, —(CH₂)₂NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂,—CH═CH—CH₂NH₂, —C≡C—CH₂NH₂, or —C≡C—CH₂NC(═N)NH₂; R² is halo, —CF₃,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —O—(CH₂)₃NH₂, —(CH₂)₃NC(═N)NH₂,—(CH₂)₂NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—CH₂NH₂, or—C≡C—CH₂NC(═N)NH₂; R³ is H, —CF₃, —O—(CH₂)₃NH₂, or —O—(CH₂)₃NC(═N)NH₂;R⁴ is H, halo, —O—(CH₂)₃NH₂, —(CH₂)₂NH₂, —(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂NC(═N)NH₂; R⁵ is H, halo, —O—(CH₂)₃NH₂, —(CH₂)₂NH₂,—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂,—C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂NC(═N)NH₂; R⁶ is H,—(CH₂)₃NH₂ or —O—(CH₂)₃NC(═N)NH₂; R⁷ is H, —(CH₂)₃NH₂ or—O—(CH₂)₃NC(═N)NH₂; R⁸ is H or halo; and R⁹ is H or halo.

In some embodiments, the compound is chosen from

or a pharmaceutically acceptable salt thereof.

In some embodiments, any one or more of the above compounds may beexcluded from any of the genus of compounds described above.

The present disclosure also provides compositions comprising one or moreof the compounds or salts described above and a pharmaceuticallyacceptable carrier.

The present disclosure also provides methods of preventing or treatingcandidiasis (oral and/or disseminated) or an aspergillus infection in amammal comprising administering to the mammal in need thereof aneffective amount of a compound of Formula VIII:

wherein:

R¹ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R² is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R³ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁴ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁵ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁶ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁷ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁸ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4; and

R⁹ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is halo, —CF₃, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—C≡C—CH₂NH₂, —(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, or—C≡C—CH₂NC(═N)NH₂. In some embodiments, R¹ is halo, —CF₃, —(CH₂)₂NH₂,—(CH₂)₃NH₂, —O—(CH₂)₃NH₂, —(CH₂)₃NC(═N)NH₂, —(CH₂)₂NC(═N)NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—CH₂NH₂, or —C≡C—CH₂NC(═N)NH₂.

In any of the above embodiments, R² is halo, —CF₃, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂,—CH═CH—CH₂NH₂, —C≡C—CH₂NH₂, or —C≡C—CH₂NC(═N)NH₂. In some embodiments,R² is halo, —CF₃, —(CH₂)₂NH₂, —(CH₂)₃NH₂, —O—(CH₂)₃NH₂,—(CH₂)₃NC(═N)NH₂, —(CH₂)₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, or —C≡C—CH₂NC(═N)NH₂.

In any of the above embodiments, R³ is H, —CF₃, —O—(CH₂)_(n)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂. In some embodiments, R³ is H, —CF₃, —O—(CH₂)₃NH₂,or —O—(CH₂)₃NC(═N)NH₂.

In any of the above embodiments, R⁴ is H, halo, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂,—CH═CH—CH₂NH₂, —C≡C—(CH₂)_(n)NH₂, or —C≡C—(CH₂)_(n)NC(═N)NH₂. In someembodiments, R⁴ is H, halo, —O—(CH₂)₃NH₂, —(CH₂)₂NH₂, —(CH₂)₂NC(═N)NH₂,—C≡C—CH₂NH₂, —CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂,—C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂NC(═N)NH₂.

In any of the above embodiments, R⁵ is H, halo, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂,—C≡C—(CH₂)_(n)NH₂, or —C≡C—(CH₂)_(n)NC(═N)NH₂. In some embodiments, R⁵is H, halo, —O—(CH₂)₃NH₂, —(CH₂)₂NH₂, —(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂NC(═N)NH₂.

In any of the above embodiments, R⁶ is H, —(CH₂)_(n)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂. In some embodiments, R⁶ is H, —(CH₂)₃NH₂, or—O—(CH₂)₃NC(═N)NH₂.

In any of the above embodiments, R⁷ is H, —(CH₂)_(n)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂. In some embodiments, R⁷ is H, —(CH₂)₃NH₂, or—O—(CH₂)₃NC(═N)NH₂.

In any of the above embodiments, R⁸ is H or halo.

In any of the above embodiments, R⁹ is H or halo.

In some embodiments, R¹ is halo, —CF₃, —(CH₂)₂NH₂, —(CH₂)₃NH₂,—O—(CH₂)₃NH₂, —(CH₂)₃NC(═N)NH₂, —(CH₂)₂NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂,—CH═CH—CH₂NH₂, —C≡C—CH₂NH₂, or —C≡C—CH₂NC(═N)NH₂; R² is halo, —CF₃,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —O—(CH₂)₃NH₂, —(CH₂)₃NC(═N)NH₂,—(CH₂)₂NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—CH₂NH₂, or—C≡C—CH₂NC(═N)NH₂; R³ is H, —CF₃, —O—(CH₂)₃NH₂, or —O—(CH₂)₃NC(═N)NH₂;R⁴ is H, halo, —O—(CH₂)₃NH₂, —(CH₂)₂NH₂, —(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂NC(═N)NH₂; R⁵ is H, halo, —O—(CH₂)₃NH₂, —(CH₂)₂NH₂,—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂,—C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂NC(═N)NH₂; R⁶ is H,—(CH₂)₃NH₂ or —O—(CH₂)₃NC(═N)NH₂; R⁷ is H, —(CH₂)₃NH₂ or—O—(CH₂)₃NC(═N)NH₂; R⁸ is H or halo; and R⁹ is H or halo.

In some embodiments, the compound is chosen from

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides methods of killing or inhibitingthe growth of a Candida or Aspergillus species comprising contacting theCandida or Aspergillus species with an effective amount of a compound ofFormula VIII:

wherein:

R¹ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—(CH₂)₂NH₂,—CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R² is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R³ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁴ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁵ is H, halo, haloalkyl, 13 NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁶ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁷ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4;

R⁸ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4; and

R⁹ is H, halo, haloalkyl, —NH₂, —C₁₋₃alkyl, —NH(CH₂)_(n)NH₂,—NH(CH₂)_(n)NC(═N)NH₂, —(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂,—O—(CH₂)_(n)NH₂, —O—(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—(CH₂)₂NH₂, —C≡C—(CH₂)₂NH₂,—CH═CH—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂—NC(═N)NH₂,where n is 2, 3, or 4; or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is halo, —CF₃, —(CH₂)_(n)NH₂, —O—(CH₂)_(n)NH₂,—C≡C—CH₂NH₂, —(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, or—C≡C—CH₂NC(═N)NH₂. In some embodiments, R¹ is halo, —CF₃, —(CH₂)₂NH₂,—(CH₂)₃NH₂, —O—(CH₂)₃NH₂, —(CH₂)₃NC(═N)NH₂, —(CH₂)₂NC(═N)NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—CH₂NH₂, or —C≡C—CH₂NC(═N)NH₂.

In any of the above embodiments, R² is halo, —CF₃, —(CH₂)_(n)NH₂,—O—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂,—CH═CH—CH₂NH₂, —C≡C—CH₂NH₂, or —C≡C—CH₂NC(═N)NH₂. In some embodiments,R² is halo, —CF₃, —(CH₂)₂NH₂, —(CH₂)₃NH₂, —O—(CH₂)₃NH₂,—(CH₂)₃NC(═N)NH₂, —(CH₂)₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, or —C≡C—CH₂NC(═N)NH₂.

In any of the above embodiments, R³ is H, —CF₃, —O—(CH₂)_(n)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂. In some embodiments, R³ is H, —CF₃, —O—(CH₂)₃NH₂,or —O—(CH₂)₃NC(═N)NH₂.

In any of the above embodiments, R⁴ is H, halo, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂,—CH═CH—CH₂NH₂, —C≡C—(CH₂)_(n)NH₂, or —C≡C—(CH₂)_(n)NC(═N)NH₂. In someembodiments, R⁴ is H, halo, —O—(CH₂)₃NH₂, —(CH₂)₂NH₂, —(CH₂)₂NC(═N)NH₂,—C≡C—CH₂NH₂, —CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂, —C≡C—(CH₂)₂NH₂,—C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂NC(═N)NH₂.

In any of the above embodiments, R⁵ is H, halo, —O—(CH₂)_(n)NH₂,—(CH₂)_(n)NH₂, —(CH₂)_(n)NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂,—C≡C—(CH₂)_(n)NH₂, or —C≡C—(CH₂)_(n)NC(═N)NH₂. In some embodiments, R⁵is H, halo, —O—(CH₂)₃NH₂, —(CH₂)₂NH₂, —(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂NC(═N)NH₂.

In any of the above embodiments, R⁶ is H, —(CH₂)_(n)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂. In some embodiments, R⁶ is H, —(CH₂)₃NH₂, or—O—(CH₂)₃NC(═N)NH₂.

In any of the above embodiments, R⁷ is H, —(CH₂)_(n)NH₂, or—O—(CH₂)_(n)NC(═N)NH₂. In some embodiments, R⁷ is H, —(CH₂)₃NH₂, or—O—(CH₂)₃NC(═N)NH₂.

In any of the above embodiments, R⁸ is H or halo.

In any of the above embodiments, R⁹ is H or halo.

In some embodiments, R¹ is halo, —CF₃, —(CH₂)₂NH₂, —(CH₂)₃NH₂,—O—(CH₂)₃NH₂, —(CH₂)₃NC(═N)NH₂, —(CH₂)₂NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂,—CH═CH—CH₂NH₂, —C≡C—CH₂NH₂, or —C≡C—CH₂NC(═N)NH₂; R² is halo, —CF₃,—(CH₂)₂NH₂, —(CH₂)₃NH₂, —O—(CH₂)₃NH₂, —(CH₂)₃NC(═N)NH₂,—(CH₂)₂NC(═N)NH₂, —CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—CH₂NH₂, or—C≡C—CH₂NC(═N)NH₂; R³ is H, —CF₃, —O—(CH₂)₃NH₂, or —O—(CH₂)₃NC(═N)NH₂;R⁴ is H, halo, —O—(CH₂)₃NH₂, —(CH₂)₂NH₂, —(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂,—CH═CH—CH₂NC(═N)NH₂, —CH═CH—CH₂NH₂, —C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂,or —C≡C—(CH₂)₂NC(═N)NH₂; R⁵ is H, halo, —O—(CH₂)₃NH₂, —(CH₂)₂NH₂,—(CH₂)₂NC(═N)NH₂, —C≡C—CH₂NH₂, —CH═CH—CH₂NH₂, —CH═CH—CH₂NC(═N)NH₂,—C≡C—(CH₂)₂NH₂, —C≡C—CH₂NC(═N)NH₂, or —C≡C—(CH₂)₂NC(═N)NH₂; R⁶ is H,—(CH₂)₃NH₂ or —O—(CH₂)₃NC(═N)NH₂; R⁷ is H, —CH₂)₃NH₂ or—O—(CH₂)₃NC(═N)NH₂; R⁸ is H or halo; and R⁹ is H or halo.

In some embodiments, the compound is chosen from

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula IX:

wherein:

each X is, independently, O or S;

each Y is, independently, O or S;

each R₂ is, independently, —C₁-C₉ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

each R₃ is, independently, —C₁-C₉ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; and

each R₄ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where n is an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each X is O.

In any of the above embodiments, each Y is O.

In any of the above embodiments, each R₂ is, independently, —C₁-C₆straight or branched alkyl optionally substituted with one or more —NH₂,—N(CH₃)₂ or —NH—C(═NH)NH₂; or each R₂ is, independently, —C₁-C₆ straightor branched alkyl; or each R₂ is, independently, —C₁-C₄ straight alkyl;or each R₂ is methyl.

In any of the above embodiments, each R₃ is, independently, —C₁-C₆straight or branched alkyl optionally substituted with one or more —NH₂,—N(CH₃)₂ or —NH—C(═NH)NH₂; or each R₃ is, independently, —C₁-C₆ straightor branched alkyl; or each R₃ is, independently, —C₃-C₅ straight orbranched alkyl; or each R₃ is —(CH₂)₂—CH(CH₃)₂.

In any of the above embodiments, each R₄ is independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where n is an integer from 1or 2; or each R₄ is, independently —(CH₂)_(n)—NH—C(═NH)NH₂, where n isan integer from 1 or 2; or each R₄ is —(CH₂)—NH—C(═NH)NH₂.

In some embodiments,

each X and Y are O;

each R₂ is, independently, —C₁-C₆ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

each R₃ is, independently, —C₁-C₆ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; and

each R₄ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where n is an integer from 1 or 2.

In some embodiments,

each X and Y are O;

each R₂ is, independently, —C₁-C₆straight or branched alkyl;

each R₃ is, independently, —C₁-C₆ straight or branched alkyl; and

each R₄ is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where n is aninteger from 1 or 2.

In some embodiments,

each R₂ is, independently, —C₁-C₄ straight alkyl;

each R₃ is, independently, —C₃-C₅ straight or branched alkyl; and

each R₄ is —(CH₂)—NH—C(═NH)NH₂.

In some embodiments,

each X and Y are O;

each R₂ is methyl;

each R₃ is —(CH₂)₂—CH(CH₃)₂; and

each R₄ is —(CH₂)—NH—C(═NH)NH₂.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides methods of preventing or treatingcandidiasis (oral and/or disseminated) or an aspergillus infection in amammal comprising administering to the mammal in need thereof aneffective amount of a compound of Formula IX:

wherein:

each X is, independently, O or S;

each Y is, independently, O or S;

each R₂ is, independently, —C₁-C₉ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

each R₃ is, independently, —C₁-C₉ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; and

each R₄ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where n is an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each X is O.

In any of the above embodiments, each Y is O.

In any of the above embodiments, each R₂ is, independently, —C₁-C₆straight or branched alkyl optionally substituted with one or more —NH₂,—N(CH₃)₂ or —NH—C(═NH)NH₂; or each R₂ is, independently, —C₁-C₆ straightor branched alkyl; or each R₂ is, independently, —C₁-C₄ straight alkyl;or each R₂ is methyl.

In any of the above embodiments, each R₃ is, independently, —C₁-C₆straight or branched alkyl optionally substituted with one or more —NH₂,—N(CH₃)₂ or —NH—C(═NH)NH₂; or each R₃ is, independently, —C₁-C₆ straightor branched alkyl; or each R₃ is, independently, —C₃-C₅ straight orbranched alkyl; or each R₃ is —(CH₂)₂—CH(CH₃)₂.

In any of the above embodiments, each R₄ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where n is an integer from 1or 2; or each R₄ is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where n isan integer from 1 or 2; or each R₄ is —(CH₂)—NH—C(═NH)NH₂.

In some embodiments,

each X and Y are O;

each R₂ is, independently, —C₁-C₆ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

each R₃ is, independently, —C₁-C₆ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; and

each R₄ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where n is an integer from 1 or 2.

In some embodiments,

each X and Y are O;

each R₂ is, independently, —C₁-C₆ straight or branched alkyl;

each R₃ is, independently, —C₁-C₆ straight or branched alkyl; and

each R₄ is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where n is aninteger from 1 or 2.

In some embodiments,

each R₂ is, independently, —C₁-C₄ straight alkyl;

each R₃ is, independently, —C₃-C₅ straight or branched alkyl; and

each R₄ is —(CH₂)—NH—C(═NH)NH₂.

In some embodiments,

each X and Y are O;

each R₂ is methyl;

each R₃ is —(CH₂)₂—CH(CH₃)₂; and

each R₄ is —(CH₂)—NH—C(═NH)NH₂.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides methods of killing or inhibitingthe growth of a Candida or Aspergillus species comprising contacting theCandida or Aspergillus species with an effective amount of a compound ofFormula IX:

wherein:

each X is, Independently, O or S;

each Y is, independently, O or S;

each R₂ is, independently, —C₁-C₉ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

each R₃ is, independently, —C₁-C₉ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; and

each R₄ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where n is an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each X is O.

In any of the above embodiments, each Y is O.

In any of the above embodiments, each R₂ is, independently, —C₁-C₆straight or branched alkyl optionally substituted with one or more —NH₂,—N(CH₃)₂ or —NH—C(═NH)NH₂; or each R₂ is, independently, —C₁-C₆ straightor branched alkyl; or each R₂ is, independently, —C₁-C₄ straight alkyl;or each R₂ is methyl.

In any of the above embodiments, each R₃ is, independently, —C₁-C₆straight or branched alkyl optionally substituted with one or more —NH₂,—N(CH₃)₂ or —NH—C(═NH)NH₂; or each R₃ is, independently, —C₁-C₆ straightor branched alkyl; or each R₃ is, independently, —C₃-C₅ straight orbranched alkyl; or each R₃ is —(CH₂)₂—CH(CH₃)₂.

In any of the above embodiments, each R₄ is, independently,—(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂, where n is an integer from 1or 2; or each R₄ is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where n isan integer from 1 or 2; or each R₄ is —(CH₂)—NH—C(═NH)NH₂.

In some embodiments,

each X and Y are O;

each R₂ is, independently, —C₁-C₆ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂;

each R₃ is, independently, —C₁-C₆ straight or branched alkyl optionallysubstituted with one or more —NH₂, —N(CH₃)₂ or —NH—C(═NH)NH₂; and

each R₄ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where n is an integer from 1 or 2.

In some embodiments,

each X and Y are O;

each R₂ is, independently, —C₁-C₆ straight or branched alkyl;

each R₃ is, independently, —C₁-C₆ straight or branched alkyl; and

each R₄ is, independently, —(CH₂)_(n)—NH—C(═NH)NH₂, where n is aninteger from 1 or 2.

In some embodiments,

each R₂ is, independently, —C₁-C₄ straight alkyl;

each R₃ is, independently, —C₃-C₅ straight or branched alkyl; and

each R₄ is —(CH₂)—NH—C(═NH)NH₂.

In some embodiments,

each X and Y are O,

each R₂ is methyl;

each R₃ is —(CH₂)₂—CH(CH₃)₂; and

each R₄ is —(CH₂)—NH—C(═NH)NH₂.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides compounds of Formula X:

wherein:

X is

and

each R¹ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where n is an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where n is 1 or 2; or each R¹ is, independently—(CH₂)_(n)—NH—C((50 NH)NH₂, where n is 1 or 2; or each R¹ is—(CH₂)₂—NHC(═NH)NH₂.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides methods of preventing or treatingcandidiasis (oral and/or disseminated) or an aspergillus infection in amammal comprising administering to the mammal in need thereof aneffective amount of a compound of Formula X:

wherein:

X is

and

each R¹ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where n is an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where n is 1 or 2; or each R¹ is, independently—(CH₂)_(n)—NH—C(═NH)NH₂, where n is 1 or 2; or each R¹ is—(CH₂)₂—NHC(═NH)NH₂.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

The present disclosure also provides methods of killing or inhibitingthe growth of a Candida or Aspergillus species comprising contacting theCandida or Aspergillus species with an effective amount of a compound ofFormula X:

wherein:

X is

and

each R¹ is, independently, —(CH₂)_(n)—NH₂ or —(CH₂)_(n)—NH—C(═NH)NH₂,where n is an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof.

In some embodiments, each R¹ is, independently, —(CH₂)_(n)—NH₂ or—(CH₂)_(n)—NH—C(═NH)NH₂, where n is 1 or 2; or each R¹ is, independently—(CH₂)_(n)—NH—C(═NH)NH₂, where n is 1 or 2; or each R¹ is—(CH₂)₂—NHC(═NH)NH₂.

In some embodiments, the compound is

or a pharmaceutically acceptable salt thereof.

In any of the above embodiments, one or more of the compounds recitedherein may be more effective (better IC₅₀ or EC₅₀ value) against aCandida species (such a C. albicans) than any one or more of E. coli25922, S. aureus 27660, E. faecalis 29212, P. aeruginosa 10145, and K.pneumoniae 13883. Thus, one or more of the compounds recited herein maybe more selective for a Candida species (such a C. albicans) than anyone or more of E. coli 25922, S. aureus 27660, E. faecalis 29212, P.aeruginosa 10145, and K. pneumoniae 13883. Some of the active compoundsdescribed herein are, thus, highly selective for C. albicans overGram-positive and Gram-negative bacteria. This may be advantageous insituations where one skilled in the art does not desire to disruptnormal flora within an individual. Thus, when administered to a mammal,any one ore more of the compounds recited herein may kill or inhibit thegrowth of Candida (such a C. albicans) or Aspergillus species withoutsignificantly disturbing the normal flora of the individual.

Polyamides and polyesters that are useful in the present disclosure canbe prepared by typical condensation polymerization and additionpolymerization processes (see, for example, G. Odian, Principles ofPolymerization, John Wiley & Sons, Third Edition (1991), and M. Steven,Polymer Chemistry, Oxford University Press (1999)). Most commonly, thepolyamides are prepared by a) thermal dehydration of amine salts ofcarboxylic acids, b) reaction of acid chlorides with amines, and c)aminolysis of esters. Methods a) and c) are of limited use inpolymerizations of aniline derivatives which are generally preparedutilizing acid chlorides. The skilled chemist, however, will recognizethat there are many alternative active acylating agents, for example,phosphoryl anhydrides, active esters or azides, which may replace anacid chloride and which, depending of the particular polymer beingprepared, may be superior to an acid chloride. The acid chloride routeis probably the most versatile and has been used extensively for thesynthesis of aromatic polyamides.

Homopolymers derived from substituted aminobenzoic acid derivatives canalso prepared in a stepwise fashion. A stepwise process comprisescoupling an N-protected amino acid to an amine (or hydroxy group) andsubsequently removing the amine-protecting group and repeating theprocess. These techniques have been highly refined for synthesis ofspecific peptides, allow for the synthesis of specific sequences, andboth solid-phase and solution techniques for peptide synthesis aredirectly applicable to the present disclosure. An alternative embodimentis the corresponding polysulfonamides that can be prepared in analogousfashion by substituting sulfonyl chlorides for carboxylic acidchlorides.

The most common method for the preparation of polyureas is the reactionof diamines with diisocyanates (see, Yamaguchi et al., Polym. Bull.,2000, 44, 247). This exothermic reaction can be carried out by solutiontechniques or by interfacial techniques. One skilled in organic andpolymer chemistry will appreciate that the diisocyanate can be replacedwith a variety of other bis-acylating agents, such as phosgene orN,N′-(diimidazolyl)carbonyl, with similar results. Polyurethanes areprepared by comparable techniques using a diisocyanate and a dialcoholor by reaction of a diamine with a bis-chloroformate.

The syntheses of compounds described herein can be carried out byroutine and/or known methods such as those disclosed in, for example,U.S. Patent Application Publication Nos. 2005-0287108, 2006-0041023,U.S. Pat. No. 7,173,102, International Publication Nos. WO 2005/123660,WO 2004/082643, and WO 2006/093813, and U.S. Application Publication No.2010-0081665, each of which is incorporated herein by reference in itsentirety. Numerous pathways are available to incorporate polar andnonpolar side chains. Phenolic groups on the monomer can be alkylated.Alkylation of the commercially available phenol will be accomplishedwith standard Williamson ether synthesis for the non-polar side chainwith ethyl bromide as the alkylating agent. Polar sidechains can beintroduced with bifunctional alkylating agents such as BOC-NH(CH₂)₂Br.Alternately, the phenol group can be alkylated to install the desiredpolar side chain function by employing the Mitsonobu reaction withBOC-NH(CH₂)₂-OH, triphenyl phosphine, and diethylacetylenedicarboxylate. Standard conditions for reduction of the nitrogroups and hydrolysis of the ester afford the amino acid. With theaniline and benzoic acid in hand, coupling can be effected under avariety of conditions. Alternatively, the hydroxy group of the(di)nitrophenol can be converted to a leaving group and a functionalityintroduced under nucleophilic aromatic substitution conditions. Otherpotential scaffolds that can be prepared with similar sequences aremethyl 2-nitro-4-hydroxybenzoate and methyl 2-hydroxy-4-nitrobenzoate.

Compounds described herein can also be synthesized by solid-phasesynthetic procedures well know to those of skill in the art (see, Tew etal., Proc. Natl. Acad. Sci. USA, 2002, 99, 5110-5114; Barany et al.,Int. J. Pept. Prot. Res., 1987, 30, 705-739, Solid-phase Synthesis: APractical Guide, Kates, S. A., and Albericio, F., eds., Marcel Dekker,New York (2000); and Dörwald, F. Z., Organic Synthesis on Solid Phase:Supports, Linkers, Reactions, 2nd Ed., Wiley-VCH, Weinheim (2002)).

The compounds described herein can also be designed using computer-aidedcomputational techniques, such as de novo design techniques, to embodythe amphiphilic properties. In general, de novo design of compounds isperformed by defining a three-dimensional framework of the backboneassembled from a repeating sequence of monomers using molecular dynamicsand quantum force field calculations. Next, side groups arecomputationally grafted onto the backbone to maximize diversity andmaintain drug-like properties. The best combinations of functionalgroups are then computationally selected to produce a cationic,amphiphilic structures. Representative compounds can be synthesized fromthis selected library to verify structures and test their biologicalactivity. Novel molecular dynamic and coarse grain modeling programshave also been developed for this approach because existing force fieldsdeveloped for biological molecules, such as peptides, were unreliable inthese oligomer applications (see, Car et al., Phys. Rev. Lett., 1985,55, 2471-2474; Siepmann et al., Mol. Phys., 1992, 75, 59-70; Martin etal., J. Phys. Chem., 1999, 103, 4508-4517; and Brooks et al., J. Comp.Chem., 1983, 4, 187-217). Several chemical structural series ofcompounds have been prepared. See, for example, InternationalPublication No. WO 2002/100295, which is incorporated herein byreference in its entirety. The compounds described herein can beprepared in a similar manner. Molecular dynamic and coarse grainmodeling programs can be used for a design approach. See, for example,U.S. Application Publication No. 2004-0107056, and U.S. ApplicationPublication No. 2004-0102941, each of which is incorporated herein byreference in its entirety.

After verifying the suitability of the force field by comparing computedpredictions of the structure and thermodynamic properties to moleculesthat have similar torsional patterns and for which experimental data areavailable, the fitted torsions can then be combined with bondstretching, bending, one-four, van der Waals, and electrostaticpotentials borrowed from the CHARMM (see, Brooks et al., J. Comp. Chem.,1983, 4, 187-217) and TraPPE (Martin et al., J. Phys. Chem., 1999, 103,4508-4517; and Wick et al., J. Phys. Chem., 2000, 104, 3093-3104)molecular dynamics force fields. To identify conformations that canadopt periodic folding patterns with polar groups and apolar groupslined up on the opposite sides, initial structures can be obtained withthe Gaussian package (see, Frisch et al., Gaussian 98 (revision A.7)Gaussian Inc., Pittsburgh, Pa. 1998). Then, the parallelized plane-waveCar-Parrinello CP-MD (see, Car et al., Phys. Rev. Lett., 1985, 55,2471-2474) program, (see Röthlisberger et al., J. Chem. Phys., 1996,3692-3700) can be used to obtain energies at the minimum and constrainedgeometries. The conformations of the compounds without side-chains canbe investigated in the gas phase. Both MD and MC methods can be used tosample the conformations. The former is useful for global motions of thecompound. With biasing techniques (see, Siepmann et al., Mol. Phys.,1992, 75, 59-70; Martin et al., J. Phys. Chem., 1999, 103, 4508-4517;and Vlugt et al., Mol. Phys., 1998, 94, 727-733), the latter allowsefficient sampling for compounds with multiple local minimumconfigurations that are separated by relatively large barriers.

The potential conformations are examined for positions to attach pendantgroups that will impart amphiphilic character to the secondarystructure. Compounds selected from the gas phase studies with suitablebackbone conformations and with side-chains at the optimal positions tointroduce amphiphilicity can be further evaluated in a model interfacialsystem. n-hexane/water can be chosen because it is simple and cheap forcalculations while it mimics well the lipid/water bilayer environment.Compound secondary structures that require intercompound interactionscan be identified by repeating the above-mentioned calculations using aperiodically repeated series of unit cells of various symmetries (socalled variable cell molecular dynamics or Monte Carlo technique) withor without solvent. The results of these calculations can guide theselection of candidates for synthesis.

The compounds described herein can be administered in any conventionalmanner by any route where they are active. Administration can besystemic, topical, or oral. For example, administration can be, but isnot limited to, parenteral, subcutaneous, intravenous, intramuscular,intraperitoneal, transdermal, oral, buccal, sublingual, or ocularroutes, or intravaginally, by inhalation, by depot injections, or byimplants. The mode of administration can depend on the pathogen ormicrobe to be targeted. The selection of the specific route ofadministration can be selected or adjusted by the clinician according tomethods known to the clinician to obtain the desired clinical response.

In some embodiments, it may be desirable to administer one or morecompounds, or a pharmaceutically acceptable salt thereof, locally to anarea in need of treatment. This may be achieved, for example, and not byway of limitation, by local infusion during surgery, topicalapplication, e.g., in conjunction with a wound dressing after surgery,by injection, by means of a catheter, by means of a suppository, or bymeans of an implant, wherein the implant is of a porous, non-porous, orgelatinous material, including membranes, such as sialastic membranes,or fibers.

The compounds described herein can be administered either alone or incombination (concurrently or serially) with other pharmaceuticals. Thecompounds can be administered in combination with anti-cancer oranti-neoplastic agents, or in combination with other cancer therapiesother than chemotherapy, such as, for example, surgery or radiotherapy.In some embodiments, the compounds described herein can also beadministered in combination with (i.e., as a combined formulation or asseparate formulations) with antibiotics (in particular, anti-yeastcompounds), such as, for example: 1) protein synthesis inhibitorsincluding, but not limited to, amikacin, anisomycin, apramycin,azithromycin, blasticidine S, brefeldin A, butirosin, chloramphenicol,chlortetracycline, clindamycin, clotrimazole, cycloheximide,demeclocycline, dibekacin, dihydrostreptomycin, doxycycline, duramycin,emetine, erythromycin, fusidic acid, G 418, gentamicin, helvolic acid,hygromycin B, josamycin, kanamycin, kirromycin, lincomycin,meclocycline, mepartricin, midecamycin, minocycline, neomycin,netilmicin, nitrofurantoin, nourseothricin, oleandomycin,oxytetracycline, paromomycin, puromycin, rapamycin, ribostamycin,rifampicin, rifamycin, rosamicin, sisomicin, spectinomycin, spiramycin,streptomycin, tetracycline, thiamphenicol, thiostrepton, tobramycin,tunicamycin, tylosin, viomycin, and virginiamycin; 2) DNA synthesisinterfering agents including, but not limited to, camptothecin,10-deacetylbaccatin III, azacytidine, 7-aminoactinomycin D,8-quinolinol, 9-dihydro-13-acetylbaccatin III, aclarubicin, actinomycinD, actinomycin I, actinomycin V, befilomycin A1, bleomycin, capreomycin,chromomycin, cinoxacin, ciprofloxacin, cis-diammineplatinum(II)dichloride, coumermycin A1, L(+)-lactic acid, cytochalasin B,cytochalasin D, dacarbazine, daunorubicin, distamycin A, doxorubicin,echinomycin, enrofloxacin, etoposide, flumequine, formycin, fumagillin,ganciclovir, gliotoxin, lomefloxacin, metronidazole, mithramycin A,mitomycin C, nalidixic acid, netropsin, nitrofurantoin, nogalamycin,nonactin, novobiocin, ofloxacin, oxolinic acid, paclitaxel, phenazine,phleomycin, pipemidic acid, rebeccamycin, sinefungin, streptonigrin,streptozocin, succinylsulfathiazole, sulfadiazine, sulfadimethoxine,sulfaguanidine purum, sulfamethazine, sulfamonomethoxine, sulfanilamide,sulfaquinoxaline, sulfasalazine, sulfathiazole, trimethoprim,tubercidin, 5-azacytidine, cordycepin, and formycin A; 3) cell wallsynthesis interfering agents including, but not limited to,(+)-6-aminopenicillanic acid, 7-Aminodesacetoxycephalosporanic acid,amoxicillin, ampicillin, azlocillin, bacitracin, carbenicillin,cefaclor, cefamandole, cefazolin, cefmetazole, cefoperazone, cefotaxime,cefsulodin, ceftriaxone, cephalexin, cephalosporin C, cephalothin,cephradine, cloxacillin, D-cycloserine, dicloxacillin, D-penicillamine,econazole, ethambutol, lysostaphin, moxalactam, nafcillin, nikkomycin Z,nitrofurantoin, oxacillin, penicillic, penicillin G, phenethicillin,phenoxymethylpenicillinic acid, phosphomycin, pipemidic acid,piperacillin, ristomycin, and vancomycin; 4) cell membrane permeabilityinterfering agents (ionophores) including, but not limited to,2-mercaptopyridine, 4-bromocalcimycin A23187, alamethicin, amphotericinB, calcimycin A23187, chlorhexidine, clotrimazole, colistin, econazole,hydrocortisone, filipin, gliotoxin, gramicidin A, gramicidin C,ionomycin, lasalocid A, lonomycin A, monensin,N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, narasin, nigericin,nisin, nonactin, nystatin, phenazine, pimaricin, polymyxin B,DL-penicillamine, polymyxin B, praziquantel, salinomycin, surfactin, andvalinomycin; 5) enzyme inhibitors including, but not limited to,(+)-usnic acid, (±)-miconazole, (S)-(+)-camptothecin,1-deoxymannojirimycin, 2-heptyl-4-hydroxyquinoline N-oxide, cordycepin,1,10-phenanthroline, 6-diazo-5-oxo-L-norleucine, 8-quinolinol,antimycin, antipain, ascomycin, azaserine, bafilomycin, cerulenin,chloroquine, cinoxacin, ciprofloxacin, mevastatin, concanamycin A,concanamycin C, coumermycin A1, L(+)-lactic acid, cyclosporin A,econazole, enrofloxacin, etoposide, flumequine, formycin A,furazolidone, fusaric acid, geldanamycin, gliotoxin, gramicidin A,gramicidin C, herbimycin A, iodomethacin, irgasan, lomefloxacin,mycophenolic acid, myxothiazol,N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, nalidixic acid,netropsin, niclosamide, nikkomycin, N-methyl-1-deoxynojirimycin,nogalamycin, nonactin, novobiocin, ofloxacin, oleandomycin, oligomycin,oxolinic acid, piericidin A, pipemidic acid, radicicol, rapamycin,rebeccamycin, sinefungin, staurosporine, stigmatellin,succinylsulfathiazole, succinylsulfathiazole, sulfadiazine,sulfadimethoxine, sulfaguanidine, sulfamethazine, sulfamonomethoxine,sulfanilamide, sulfaquinoxaline, sulfasalazine, sulfathiazole, triacsinC, trimethoprim, and vineomycin A1; and 6) membrane modifiers including,but not limited to, paracelsin. In some embodiments, one or morecompounds described herein can be administered in combination with oneor more anti-fungal drugs, such as nystatin, miconazole, Gentian violet,or amphotericin B.

The means and methods for administration are known in the art and anartisan can refer to various pharmacologic references for guidance (see,for example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc.(1979); and Goodman & Gilman's The Pharmaceutical Basis of Therapeutics,6th Edition, MacMillan Publishing Co., New York (1980)).

The amount of compound to be administered is that amount which istherapeutically effective. The dosage to be administered will depend onthe characteristics of the subject being treated, e.g., the particularanimal treated, age, weight, health, types of concurrent treatment, ifany, and frequency of treatments, and can be easily determined by oneskill in the art (e.g., by the clinician). The standard dosing forprotamine can be used and adjusted (i.e., increased or decreased)depending upon the the factors described above. The selection of thespecific dose regimen can be selected or adjusted or titrated by theclinician according to methods known to the clinician to obtain thedesired clinical response.

The amount of a compound described herein that will be effective in thetreatment and/or prevention of a particular disease, condition, ordisorder will depend on the nature and extend of the disease, condition,or disorder, and can be determined by standard clinical techniques. Inaddition, in vitro or in vivo assays may optionally be employed to helpidentify optimal dosage ranges. The precise dose to be employed in thecompositions will also depend on the route of administration, and theseriousness of the disorder, and should be decided according to thejudgment of the practitioner and each patient's circumstances. However,a suitable dosage range for oral administration is, generally, fromabout 0.001 milligram to about 200 milligrams per kilogram body weight,from about 0.01 milligram to about 100 milligrams per kilogram bodyweight, from about 0.01 milligram to about 70 milligrams per kilogramsbody weight, from about 0.1 milligram to about 50 milligrams perkilogram body weight, from 0.5 milligram to about 20 milligrams perkilogram body weight, or from about 1 milligram to about 10 milligramsper kilogram body weight. In some embodiments, the oral dose is about 5milligrams per kilogram body weight.

In some embodiments, suitable dosage ranges for intravenous (i.v.)administration are from about 0.01 mg to about 500 mg per kg bodyweight, from about 0.1 mg to about 100 mg per kg body weight, from about1 mg to about 50 mg per kg body weight, or from about 10 mg to about 35mg per kg body weight. Suitable dosage ranges for other modes ofadministration can be calculated based on the forgoing dosages as knownby those skilled in the art. For example, recommended dosages forintradermal, intramuscular, intraperitoneal, subcutaneous, epidural,sublingual, intracerebral, intravaginal, transdermal administration oradministration by inhalation are in the range of from about 0.001 mg toabout 200 mg per kg of body weight, from about 0.01 mg to about 100 mgper kg of body weight, from about 0.1 mg to about 50 mg per kg of bodyweight, or from about 1 mg to about 20 mg per kg of body weight.Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems. Such animal models andsystems are well known in the art.

The compounds described herein can be formulated for parenteraladministration by injection, such as by bolus injection or continuousinfusion. The compounds can be administered by continuous infusionsubcutaneously over a period of about 15 minutes to about 24 hours.Formulations for injection can be presented in unit dosage form, such asin ampoules or in multi-dose containers, with an added preservative. Thecompositions can take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles, and can contain formulatory agents such assuspending, stabilizing and/or disposing agents. In some embodiments,the injectable is in the form of short-acting, depot, or implant andpellet forms injected subcutaneously or intramuscularly. In someembodiments, the parenteral dosage form is the form of a solution,suspension, emulsion, or dry powder.

For oral administration, the compounds described herein can beformulated by combining the compounds with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds to beformulated as tablets, pills, dragees, capsules, emulsions, liquids,gels, syrups, caches, pellets, powders, granules, slurries, lozenges,aqueous or oily suspensions, and the like, for oral ingestion by apatient to be treated. Pharmaceutical preparations for oral use can beobtained by, for example, adding a solid excipient, optionally grindingthe resulting mixture, and processing the mixture of granules, afteradding suitable auxiliaries, if desired, to obtain tablets or drageecores. Suitable excipients include, but are not limited to, fillers suchas sugars, including, but not limited to, lactose, sucrose, mannitol,and sorbitol; cellulose preparations such as, but not limited to, maizestarch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and polyvinylpyrrolidone (PVP). If desired,disintegrating agents can be added, such as, but not limited to, thecross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof such as sodium alginate.

Orally administered compositions can contain one or more optionalagents, for example, sweetening agents such as fructose, aspartame orsaccharin; flavoring agents such as peppermint, oil of wintergreen, orcherry; coloring agents; and preserving agents, to provide apharmaceutically palatable preparation. Moreover, where in tablet orpill form, the compositions may be coated to delay disintegration andabsorption in the gastrointestinal tract thereby providing a sustainedaction over an extended period of time. Selectively permeable membranessurrounding an osmotically active driving compound are also suitable fororally administered compounds. Oral compositions can include standardvehicles such as mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, cellulose, magnesium carbonate, etc. Such vehicles aresuitably of pharmaceutical grade.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include, but arenot limited to, push-fit capsules made of gelatin, as well as soft,sealed capsules made of gelatin and a plasticizer, such as glycerol orsorbitol. The push-fit capsules can contain the active ingredients inadmixture with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizer. In soft capsules, the active compounds can be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers can be added.

For buccal administration, the compositions can take the form of, suchas, tablets or lozenges formulated in a conventional manner.

For administration by inhalation, the compounds described herein can bedelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebulizer, with the use of a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, such as gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds described herein can also be formulated in rectalcompositions such as suppositories or retention enemas, such ascontaining conventional suppository bases such as cocoa butter or otherglycerides. The compounds described herein can also be formulated invaginal compositions such as vaginal creams, suppositories, pessaries,vaginal rings, and intrauterine devices.

In transdermal administration, the compounds can be applied to aplaster, or can be applied by transdermal, therapeutic systems that areconsequently supplied to the organism. In some embodiments, thecompounds are present in creams, solutions, powders, fluid emulsions,fluid suspensions, semi-solids, ointments, pastes, gels, jellies, andfoams, or in patches containing any of the same.

The compounds described herein can also be formulated as a depotpreparation. Such long acting formulations can be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Depot injections can be administered at about 1to about 6 months or longer intervals. Thus, for example, the compoundscan be formulated with suitable polymeric or hydrophobic materials (forexample as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

In yet another embodiment, the compounds can be delivered in acontrolled release system. In one embodiment, a pump may be used (seeLanger, supra; Sefton, CRC Crit. Ref. Biomed. Eng., 1987, 14, 201;Buchwald et al., Surgery, 1980, 88, 507 Saudek et al., N. Engl. J. Med.,1989, 321, 574). In another embodiment, polymeric materials can be used(see Medical Applications of Controlled Release, Langer and Wise (eds.),CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability,Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NewYork (1984); Ranger et al., J. Macromol. Sci. Rev. Macromol. Chem.,1983, 23, 61; see, also Levy et al., Science, 1985, 228, 190; During etal., Ann. Neurol., 1989, 25, 351; Howard et al., J. Neurosurg., 1989,71, 105). In yet another embodiment, a controlled-release system can beplaced in proximity of the target of the compounds described herein,such as the liver, thus requiring only a fraction of the systemic dose(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systemsdiscussed in the review by Langer, Science, 1990, 249, 1527-1533) may beused.

It is also known in the art that the compounds can be contained in suchformulations with pharmaceutically acceptable diluents, fillers,disintegrants, binders, lubricants, surfactants, hydrophobic vehicles,water soluble vehicles, emulsifiers, buffers, humectants, moisturizers,solubilizers, preservatives and the like. The pharmaceuticalcompositions can also comprise suitable solid or gel phase carriers orexcipients. Examples of such carriers or excipients include, but are notlimited to, calcium carbonate, calcium phosphate, various sugars,starches, cellulose derivatives, gelatin, and polymers such aspolyethylene glycols. In some embodiments, the compounds describedherein can be used with agents including, but not limited to, topicalanalgesics (e.g., lidocaine), barrier devices (e.g., GelClair), orrinses (e.g., Caphosol).

In some embodiments, the compounds described herein can be delivered ina vesicle, in particular a liposome (see, Langer, Science, 1990, 249,1527-1533; Treat et al., in Liposomes in the Therapy of InfectiousDisease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York,pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid.).

Suitable compositions include, but are not limited to, oral non-absorbedcompositions. Suitable compositions also include, but are not limited tosaline, water, cyclodextrin solutions, and buffered solutions of pH 3-9.

The compounds described herein, or pharmaceutically acceptable saltsthereof, can be formulated with numerous excipients including, but notlimited to, purified water, propylene glycol, PEG 400, glycerin, DMA,ethanol, benzyl alcohol, citric acid/sodium citrate (pH3), citricacid/sodium citrate (pH5), tris(hydroxymethyl)amino methane HCl (pH7.0),0.9% saline, and 1.2% saline, and any combination thereof. In someembodiments, excipient is chosen from propylene glycol, purified water,and glycerin.

In some embodiments, the excipient is a multi-component system chosenfrom 20% w/v propylene glycol in saline, 30% w/v propylene glycol insaline, 40% w/v propylene glycol in saline, 50% w/v propylene glycol insaline, 15% w/v propylene glycol in purified water, 30% w/v propyleneglycol in purified water, 50% w/v propylene glycol in purified water,30% w/v propylene glycol in purified water, 50% w/v propylene glycol inpurified water, 30% w/v propylene glycol and 5 w/v ethanol in purifiedwater, 15% w/v glycerin in purified water, 30% w/v glycerin in purifiedwater, 50% w/v glycerin in purified water, 20% w/v Kleptose in purifiedwater, 40% w/v Kleptose in purified water, and 25% w/v Captisol inpurified water. In some embodiments, the excipient is chosen from 50%w/v propylene glycol in purified water, 15% w/v glycerin in purifiedwater, 20% w/v Kleptose in purified water, 40% w/v Kleptose in purifiedwater, and 25% w/v Captisol in purified water. In some embodiments, theexcipient is chosen from 20% w/v Kleptose in purified water, 20% w/vpropylene glycol in purified water, and 15% w/v glycerin in purifiedwater.

In some embodiments, the composition comprises 50 mg/mL of compound in20% w/v Kleptose in purified water.

In some embodiments, the formulation can be lyophilized to a solid andreconstituted with, for example, water prior to use.

When administered to a mammal (e.g., to an animal for veterinary use orto a human for clinical use) the compounds can be administered inisolated form.

When administered to a human, the compounds can be sterile. Water may bea suitable carrier when a compound is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid carriers, particularly for injectable solutions.Suitable pharmaceutical carriers also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. The present compositions, if desired, can also contain minoramounts of wetting or emulsifying agents, or pH buffering agents.

The compositions described herein can take the form of a solution,suspension, emulsion, tablet, pill, pellet, capsule, capsule containinga liquid, powder, sustained-release formulation, suppository, aerosol,spray, or any other form suitable for use. Examples of suitablepharmaceutical carriers are described in Remington's PharmaceuticalSciences, A. R. Gennaro (Editor) Mack Publishing Co.

In one embodiment, the compounds are formulated in accordance withroutine procedures as a pharmaceutical composition adapted foradministration to humans. Typically, compounds are solutions in sterileisotonic aqueous buffer. Where necessary, the compositions can alsoinclude a solubilizing agent. Compositions for intravenousadministration may optionally include a local anesthetic such aslidocaine to ease pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form, for example, as a dry lophilized powder or water freeconcentrate in a hermetically sealed container such as an ampoule orsachette indicating the quantity of active agent. Where the compound isto be administered by infusion, it can be dispensed, for example, withan infusion bottle containing sterile pharmaceutical grade water orsaline. Where the compound is administered by injection, an ampoule ofsterile water for injection or saline can be provided so that theingredients may be mixed prior to administration.

The pharmaceutical compositions can be in unit dosage form. In suchform, the composition can be divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofthe preparations, for example, packeted tablets, capsules, and powdersin vials or ampules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of thesepackaged forms.

In some embodiments, a composition of the present disclosure is in theform of a liquid wherein the active agent is present in solution, insuspension, as an emulsion, or as a solution/suspension. In someembodiments, the liquid composition is in the form of a gel. In otherembodiments, the liquid composition is aqueous. In other embodiments,the composition is in the form of an ointment.

Suitable preservatives include, but are not limited to,mercury-containing substances such as phenylmercuric salts (e.g.,phenylmercuric acetate, borate and nitrate) and thimerosal; stabilizedchlorine dioxide; quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride;imidazolidinyl urea; parabens such as methylparaben, ethylparaben,propylparaben and butylparaben, and salts thereof; phenoxyethanol;chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol;phenylethyl alcohol; disodium EDTA; and sorbic acid and salts thereof.

Optionally one or more stabilizers can be included in the compositionsto enhance chemical stability where required. Suitable stabilizersinclude, but are not limited to, chelating agents or complexing agents,such as, for example, the calcium complexing agent ethylene diaminetetraacetic acid (EDTA). For example, an appropriate amount of EDTA or asalt thereof, e.g., the disodium salt, can be included in thecomposition to complex excess calcium ions and prevent gel formationduring storage. EDTA or a salt thereof can suitably be included in anamount of about 0.01% to about 0.5%. In those embodiments containing apreservative other than EDTA, the EDTA or a salt thereof, moreparticularly disodium EDTA, can be present in an amount of about 0.025%to about 0.1% by weight.

One or more antioxidants can also be included in the compositions.Suitable antioxidants include, but are not limited to, ascorbic acid,sodium metabisulfite, sodium bisulfite, acetylcysteine,polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol,methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium,sorbic acid, or other agents know to those of skill in the art. Suchpreservatives are typically employed at a level of from about 0.001% toabout 1.0% by weight.

In some embodiments, the compounds are solubilized at least in part by asolubilizing agent, Certain acceptable nonionic surfactants, for examplepolysorbate 80, can be useful as solubilizing agents, as canophthalmically acceptable glycols, polyglycols, e.g., polyethyleneglycol 400 (PEG-400), and glycol ethers.

Suitable solubilizing agents for solution and solution/suspensioncompositions are cyclodextrins. Suitable cyclodextrins can be chosenfrom α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, alkylcyclodextrins(e.g., methyl-β-cyclodextrin, dimethyl-β-cyclodextrin,diethyl-β-cyclodextrin), hydroxyalkylcyclodextrins (e.g.,hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin),carboxy-alkylcyclodextrins (e.g., carboxymethyl-β-cyclodextrin),sulfoalkylether cyclodextrins (e.g., sulfobutylether-β-cyclodextrin),and the like. Ophthalmic applications of cyclodextrins have beenreviewed in Rajewski et al., Journal of Pharmaceutical Sciences, 1996,85, 1155-1159. A cyclodextrin can optionally be present in an ophthalmiccomposition at a concentration from about 1 to about 20 mg/ml, fromabout 5 to about 100 mg/ml, or from about 10 to about 50 mg/ml.

In some embodiments, the composition optionally contains a suspendingagent, For example, in those embodiments in which the composition is anaqueous suspension or solution/suspension, the composition can containone or more polymers as suspending agents. Useful polymers include, butare not limited to, water-soluble polymers such as cellulosic polymers,for example, hydroxypropyl methylcellulose, and water-insoluble polymerssuch as cross-linked carboxyl-containing polymers.

One or more acceptable pH adjusting agents and/or buffering agents canbe included in the compositions, including acids such as acetic, boric,citric, lactic, phosphoric and hydrochloric acids; bases such as sodiumhydroxide, sodium phosphate, sodium borate, sodium citrate, sodiumacetate, sodium lactate and tris-hydroxymethylaminomethane; and bufferssuch as citrate/dextrose, sodium bicarbonate and ammonium chloride. Suchacids, bases and buffers are included in an amount required to maintainpH of the composition in an ophthalmically acceptable range.

One or more acceptable salts can be included in the compositionsdescribed herein in an amount required to bring osmolality of thecomposition into an acceptable range. Such salts include, but are notlimited to, those having sodium, potassium or ammonium cations andchloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate,thiosulfate or bisulfite anions. In some embodiment, salts includesodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate. In some embodiments, the salt is sodiumchloride.

Optionally one or more acceptable surfactants, preferably nonionicsurfactants, or co-solvents can be included in the compositions toenhance solubility of the components of the compositions or to impartphysical stability, or for other purposes. Suitable nonionic surfactantsinclude, but are not limited to, polyoxyethylene fatty acid glyceridesand vegetable oils. e.g., polyoxyethylene (60) hydrogenated castor oil;and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol10, octoxynol 40; polysorbate 20, 60 and 80;polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic® F-68, F84and P-103); cyclodextrin; or other agents known to those of skill in theart. Typically, such co-solvents or surfactants are employed in thecompositions at a level of from about 0.01% to about 2% by weight.

One or more lubricating agents can also be included optionally in thecompositions. Such agents include, but are not limited to, polyvinylalcohol, methylcellulose, hydroxypropyl methylcellulose,polyvinylpyrrolidone, and the like.

Compositions of the present disclosure typically include a combinationof one or more of the optional excipients listed above. For example, insome embodiments, the ophthalmic composition can optionally furthercomprise glycerin in an amount from about 0.5% to about 5%, from about1% to about 2.5%, or from about 1.5% to about 2% by weight. Glycerin canbe useful to increase viscosity of the composition and for adjustment ofosmolality. Independently of the presence of glycerin, the compositioncan also further comprise a cyclodextrin, such ashydroxypropyl-β-cyclodextrin, in an amount from about 0.5% to about 2.5%by weight, as a solubilizing agent, and an antimicrobially effectiveamount of a preservative, e.g., imidazolidinyl urea in an amount fromabout 0.03% to about 0.5%; methylparaben in an amount from about 0.015%to about 0.25%; propylparaben in an amount from about 0.005% to about0.01%; phenoxyethanol in an amount from about 0.25% to about 1%;disodium EDTA in an amount from about 0.05% to about 0.2%; thimerosal inan amount from 0.001% to about 0.15%; chlorobutanol in an amount fromabout 0.1% to about 0.5%; and/or sorbic acid in an amount from about0.05% to about 0.2%; all by weight.

The compounds described herein can also be incorporated intocompositions such as, for example, polishes, paints, sprays, ordetergents formulated for application to a surface to inhibit the growthof a Candida or Aspergillus species thereon. These surfaces include, butare not limited to, countertops, desks, chairs, laboratory benches,tables, floors, bed stands, tools, equipment, doorknobs, windows, andthe like. The compounds described herein can also be incorporated intosoaps and hand lotions. The present compositions, including thecleansers, polishes, paints, sprays, soaps, and detergents, can containone or more of the compounds described herein. In addition, thecompositions can optionally contain one or more of each of thefollowing: solvents, carriers, thickeners, pigments, fragrances,deodorizers, emulsifiers, surfactant, wetting agents, waxes, and/oroils. For example, in some embodiments, the compounds can beincorporated into a formulation for external use as a pharmaceuticallyacceptable skin cleanser, particularly for the surfaces of human hands.Cleansers, polishes, paints, sprays, soaps, hand lotions, and detergentsand the like containing the compounds described herein can be useful inhomes and institutions, particularly but not exclusively, in hospitalsettings for the prevention of nosocomial infections.

The present disclosure also provides pharmaceutical packs or kitscomprising one or more containers filled with one or more compoundsdescribed herein. Optionally associated with such container(s) can be anotice in the form prescribed by a governmental agency regulating themanufacture, use or sale of pharmaceuticals or biological products,which notice reflects approval by the agency of manufacture, use or salefor human administration for treating a condition, disease, or disorderdescribed herein. In some embodiments, the kit contains more than onecompound described herein. In some embodiments, the kit comprises acompound described herein in a single injectable dosage form, such as asingle dose within an injectable device such as a syringe with a needle.

The present disclosure also provides methods of inhibiting the growth ofa Candida or Aspergillus species comprising contacting the Candida orAspergillus species with one or more compounds described above, or apharmaceutically acceptable salt thereof. In some embodiments, thecompound can act as an antiseptic agent for cleansing surfaces, such asin, for example, kitchens and bathrooms. In these embodiments, thecompound can be formulated for such uses by procedures well known to theskilled artisan.

The present disclosure also provides methods of treating a mammal havingoral candidiasis comprising administering to the mammal in need thereofan effective amount of one or more compounds described above, or apharmaceutically acceptable salt thereof. In some embodiments, themammal can be pre-diagnosed with oral candidiasis prior to treatment. Insome embodiments, no formal diagnosis may have been made; in suchembodiments, the mammal may be suspected of having oral candidiasis forwhich treatment is recognized as being desirable.

In some embodiments, the yeast is, or the oral or disseminatedcandidiasis infection is due to, Candida albicans, Candida glabrata,Candida tropicalis, or Candida krusei.

The present disclosure also provides one or more compounds describedabove, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising one or more compounds describedabove, for treating candidiasis (oral and/or disseminated) or anAspergillus infection.

The present disclosure also provides one or more compounds describedabove, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising one or more compounds describedabove, for use in the manufacture of a medicament for treatingcandidiasis (oral and/or disseminated) or an Aspergillus infection.

The present disclosure also provides the use of one or more compoundsdescribed above, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising one or more compounds describedabove, in the inhibition of growth of a Candida or Aspergillus species.

The present disclosure also provides the use of one or more compoundsdescribed above, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising one or more compounds describedabove, for treating candidiasis (oral and/or disseminated) or anAspergillus infection in a mammal.

In some embodiments, the compositions are administered with ananti-microbial agent, such as, e.g., an anti-bacterial, anti-fungal,anti-mold, or anti-viral agent. For example, the anti-microbial agentcan be a second compound disclosed herein, or the anti-microbial agentcan be another anti-microbial agent such as, for example, an antibioticselected from the group consisting of aminoglycosides, cephalosporins,diaminopyridines, fluoroquinolones, sulfonamides and tetracyclines.Examples of useful antibiotics which can serve as additionalanti-microbials include, but are not limited to, amikacin, azithromycin,cefixime, cefoperazone, cefotaxime, ceftazidime, ceftizoxime,ceftriaxone, chloramphenicol, ciprofloxacin, clindamycin, colistin,domeclocycline, doxycycline, erythromycin, gentamicin, mafenide,methacycline, minocycline, neomycin, norfloxacin, ofloxacin,oxytetracycline, polymyxin B, pyrimethamine, silver sulfadiazine,sulfacetamide, sulfisoxazole, tetracycline, tobramycin, andtrimethoprim.

In those embodiments in which the composition is administered with ananti-microbial agent, the present disclosure provides administration atthe same time or sequentially, of a composition comprising one or moreof the compounds disclosed herein and a separate composition of theanti-microbial agent, in a treatment regimen intended to provide abeneficial effect from co-action of the two types of anti-microbialagents. “Co-formulation” herein means that the compound and theadditional anti-microbial agent are administered as components of asingle composition.

Any medicament having utility in treating oral candidiasis can be usedin co-therapy, co-administration, or co-formulation with a compositiondescribed above. Such additional medicaments include, but are notlimited to, anti-inflammatory agents (e.g., steroidal anti-inflammatoryagents, non-steroidal anti-inflammatory agents (NSAIDs), and selectivecyclooxygenase-2 inhibitors); topical and/or regional anesthetic agents;anti-allergic agents (e.g., anti-histamines); demulcents; acetylcholineblocking agents; adrenergic agonists, beta-adrenergic blocking agentsand other anti-glaucoma agents; anti-hypertensives; anti-cataractagents; anti-microbial agents, and anti-allergic agents.

Examples of suitable non-steroidal anti-inflammatory agents include, butare not limited to, prostaglandin H synthetase inhibitors (Cos I or CoxII), also referred to as cyclooxygenase type I and type II inhibitors,such as diclofenac, flurbiprofen, ketorolac, suprofen, nepafenac,amfenac, indomethacin, naproxen, ibuprofen, bromfenac, ketoprofen,meclofenamate, piroxicam, sulindac, mefanamic acid, diflusinal,oxaprozin, tolmetin, fenoprofen, benoxaprofen, nabumetome, etodolac,phenylbutazone, aspirin, oxyphenbutazone, tenoxicam and carprofen;cyclooxygenase type II selective inhibitors, such as vioxx, celecoxib,etodolac; PAF antagonists, such as apafant, bepafant, minopafant,nupafant and modipafant; PDE IV inhibitors, such as ariflo,torbafylline, rolipram, filaminast, piclamilast, cipamfylline, androflumilast; inhibitors of cytokine production, such as inhibitors ofthe NFkB transcription factor; or other anti-inflammatory agents know tothose skilled in the art.

Examples of suitable topical or regional anesthetic agents include, butare not limited to, benzocaine.

Examples of suitable anti-allergic agents include, but are not limitedto, pemirolast, olopatadine, and the corticosteroids (prednisolone,fluorometholone, loteprenol and dexamthasone).

Frequency of administration is typically such that the dosing interval,for example, the period of time between one dose and the next, duringwaking hours is from about 2 to about 12 hours, from about 3 to about 8hours, or from about 4 to about 6 hours. It will be understood by thoseof skill in the art that an appropriate dosing interval is dependent tosome degree on the length of time for which the selected composition iscapable of maintaining a concentration of the compound(s) in thelacrimal fluid and/or in the target tissue (e.g., the conjunctiva) abovethe MIC₉₀ (the minimum concentration of the oligomer or polymer whichinhibits microbial growth by 90%). Ideally the concentration remainsabove the MIC₉₀ for at least 100% of the dosing interval. Where this isnot achievable it is desired that the concentration should remain abovethe MIC₉₀ for at least about 60% of the dosing interval, or shouldremain above the MIC₉₀ for at least about 40% of the dosing interval.

The activity of anti-microbials is generally expressed as the minimumconcentration of a compound (active agent) required to inhibit thegrowth of a specified pathogen. This concentration is also referred toas the “minimum inhibitory concentration” or “MIC”. The term “MIC₉₀”refers to the minimum concentration of an antimicrobial active agentrequired to inhibit the growth of ninety percent (90%) of the testedisolates for one particular organism. The concentration of a compoundrequired to totally kill a specified bacterial species is referred to asthe “minimum bactericidal concentration” or “MBC.”

In some embodiments, an effective concentration of the compound in thecomposition will generally be from about 0.01% to about 20% by weight(wt %) of the composition, from about 0.05% to about 10% by weight, fromabout 0.1% to about 8.0% by weight, from about 0.5% to about 5.0% byweight, from about 1.0% to about 5.0% by weight, or from about 2.0% toabout 4.0% of the composition.

In some embodiments, the animal being treated, such as a human, is “inneed thereof.” That is, the animal is in need of treatment. Thus, insome embodiments, the animal is treated for the purpose of preventing ortreating the Candida or Aspergillus infection. In some embodiments, theanimal has been diagnosed with a Candida or Aspergillus infection or issuspected of having a Candida or Aspergillus infection. In someembodiments, the animal, or human, is in a population at risk of havinga Candida or Aspergillus infection, such as in a prison or hospital.

In order that the present disclosure may be more efficiently understood,examples are provided below. It should be understood that these examplesare for illustrative purposes only and are not to be construed aslimiting the disclosure in any manner. Throughout these examples,molecular cloning reactions, and other standard recombinant DNAtechniques, were carried out according to methods described in Maniatiset al., Molecular Cloning—A Laboratory Manual, 2nd ed., Cold SpringHarbor Press (1989), using commercially available reagents, except whereotherwise noted.

EXAMPLES Example 1 Screen for Anti-Candida Activity

Over 800 compounds were screened at a single concentration of 10 μMagainst a clinical isolate of C. albicans GDH2346 (see, triangles inFIG. 1 below), and an additional 400 compounds were screened with 11concentrations to give an IC₅₀ (see, green squares in FIG. 1 below). Theactivity was determined at 24 and 48 hours by OD₆₀₀ and fluorescence.

106 compounds showed greater than 90% inhibition, giving a hit rate of12%. These compounds are all cidal. 109 compounds showed an IC₅₀<5 μg/mLand an additional 90 had an IC₅₀<10 μg/mL.

Example 2 Activity Against Hyphae

C. albicans (GDH2346) was grown in 10% FCS for 3 days to achieve hyphae.Hyphae were treated with Compound 100 (8 μg/mL) for 0 minutes (see, FIG.2A), 15 minutes (see, FIG. 2B), 30 minutes (see, FIG. 2C), or 60 minutes(see, FIG. 2D). Cultures were stained with FungaLight Live-Dead stain(InVitrogen) and observed under fluorescence microscopy (100×magnification).

Compound 100 rapidly caused death of hyphal cultures at lowconcentrations.

Example 3 Permeabilization

(A) C. albicans GDH2346 was treated with Compound 100 at theconcentrations indicated (μg/mL) for 30 minutes, followed by stainingwith PI and quantification by flow cytometry. Ethanol treatment was usedto establish 100% uptake.

(B) Cells were treated with Compound 100 at 32 μg/mL for the timesindicated.

To determine whether the compounds act at the membrane, like many hostdefense proteins, or intracellularly like histatins, the ability ofCompound 100 to cause membrane permeability was assessed. Dose-dependentmembrane permeabilization of Candida, as shown by cellular accumulationof PI, was evident within 30 minutes at 8 to 32 μg/mL Compound 100concentrations (see FIG. 3A). Influx was rapid, where >75% of cells werepermeabilized after a 5-minute treatment with Compound 100 at 32 μg/mL(see FIG. 3B).

Example 4 Cellular Efflux-ATP Release

(A) C. albicans GDH2346 was treated with either Compound 100 or histatin5 for 30 minutes, followed by the separation of the extracellular mediumand the cells. Intracellular and extracellular ATP levels werequantified by luciferase assay and measurement in a luminometer,relative to a standard control. Treatment 1=no treatment; Treatment 2=16μg/mL Compound 100; Treatment 3=32 μg/mL Compound 100; and Treatment4=Histatin 5 (1 mg/mL).

(B) Time dependent release of ATP of cells treated with Compound 100 at32 μg/mL.

(C) Dose response of cells treated for 30 minutes, followed byquantification of extracellular ATP.

To demonstrate efflux, effects of Compound 100 on ATP release wereexamined. Cells were treated with either Compound 100 or Histatin 5, andlevels of intracellular and extracellular ATP were measured after 30minutes. At 32 μg/mL Compound 100, almost all of the ATP from the cellwas extracellular, which exceeded efflux with 1 mg/mL of histatin 5(see, FIG. 4A).

At 32 μg/mL, ATP efflux was rapid with significant extracellularaccumulation occurring by 20 minutes following treatment (see, FIG. 4B).

Efflux was also dose-dependent over 30 minutes of exposure time, withdetectable ATP levels evident at 16 μg/mL (see, FIG. 4C).

Example 5 IC₅₀ Profiles

Candida IC₅₀s were determined by OD₆₀₀ and fluorescence from vegetativecells and by MTS viability assay in the hyphal state. MICs weredetermined using a broth microdilution assay under standard CLSIconditions Bacteria strains: E. coli 25922 (EC), S. aureus 27660 (SA),E. faecalis 29212 (EF), P. aeruginosa 10145 (PA), and K. pneumoniae13883 (KP). Cytotoxicity (EC₅₀) was determined against mouse 3T3fibroblasts, human transformed liver HepG2 cells, and human oralkeratinocyte cell line, OKF6/TERT using an MTS viability assay. CandidaIC₅₀s<10 μg/mL, MICs<5 μg/mL and cytotoxicity EC₅₀s>100 μM are indicatedin green. MICs>5 μg/mL and cytotoxicity EC₅₀s<100 μM are indicated inred. Results are shown in Table 1 below.

TABLE 1 Compound Activity 100 114 136 138 135 137 115 IC50 Candida, 4.937.57 4.24 4.10 1.44 1.89 4.74 Vegetative IC50 Candida, 4.90 3.17 0.717.50 2.68 2.29 4.07 Hyphal (μg/ml) EC50 EC (μg/ml) 1.56 >50 >50 >50 6.2550 >50 EC50 SA 0.78 50 0.39 >50 12.5 25 >50 EC50 EF (μg/ml) 0.78 250.098 >50 12.5 25 >50 EC50 PA 3.13 >50 50 >50 >50 50 >50 EC50 KP1.56 >50 50 >50 12.5 >50 >50 IC50 NIH3T3 (μM) 439 543 311 406 436 83 358IC50 HepG2 >1000 255 453 502 885 182 >1000 IC50 OKF6/ >1000 172 466 491766 42 309 TERT (μM)

Example 6 IC₅₀ Profiles

Candida IC₅₀s (CA) were determined by OD₆₀₀ and fluorescence fromvegetative cells. MICs were determined using a broth microdilution assayunder standard CLSI conditions Bacteria strains: E. coli 25922 (EC), S.aureus 27660 (SA), E. faecalis 29212 (EF), P. aeruginosa 10145 (PA), andK. pneumoniae 13883 (KP). Cytotoxicity (EC₅₀) was determined againstmouse 3T3 fibroblasts and human transformed liver HepG2 cells using MTSviability assay. Results are shown in Table 2 below.

TABLE 2 CA 3T3 HepG2 EC SA EF PA KP Compound μg/mL μM μM μg/mL μg/mLμg/mL μg/mL μg/mL 139 >100 117 3.10 118 3.64 40 90 119 6.17 140 3.58 15999 0.78 0.195 3.13 3.13 3.13 141 107 62 12.5 12.5 100 25 142 1.65 131100 3.13 1.56 6.25 25 3.13 143 6.48 222 140 3.13 0.39 1.56 50 6.25 1443.95 80 188 3.13 0.098 0.195 3.13 6.25 145 23.94 >1000 790 >50 25 3.1350 >50 146 44.59 307 341 50 0.39 0.39 12.5 >50 147 1.56 0.098 0.39 6.251.56 148 8.74 450 312 25 3.13 >50 >50 >50 149 >100 29 20 3.13 0.0491.56 >100 3.13 150 3.34 54 58 0.78 0.049 1.56 3.13 3.13 151 3.85 56 783.13 0.195 6.25 6.25 12.5 152 3.77 34 12 1.56 0.39 1.56 3.13 1.56 153 4665 12.5 1.56 12.5 100 12.5 154 1.88 451 853 1.56 0.39 6.25 12.5 6.25 1552.63 12.5 0.39 >50 12.5 >50 156 1.94 487 >1000 1.56 1.56 >50 12.5 >50157 6.21 228 3.13 0.39 12.5 12.5 12.5 158 17.47 179 615 1.56 1.56 >5025 >50 159 2.11 61 64 0.78 0.78 3.13 6.25 3.13 160 1.48 28 28 1.56 1.953.13 6.25 3.13 161 11.8 356 466 1.56 6.25 >50 50 6.25 162 3.12 49 2731.56 0.39 12.5 3.13 3.13 163 1.79 31 113 3.13 3.13 3.13 50 25

Example 7 Efficacy In a Mouse Model of Oral Candidiasis

8-week old male mBD-1 (−/−) mice on a C57B1/6 background werepre-treated for 5 days with 2.5 mg/mL oral tetracycline to reduce normaloral flora (n=5 per group; n=4 for nystatin group). Day 0: infectioninitiated by oral inoculation of a 50 μL suspension of C. albicans(clinical isolate GDH2346 at 5×10⁷ cfu/mL) onto a cotton ball afterlightly scoring the tongues. Day 3: Single topical administration oftest agent (10 mg/mL) applied in 0.05 mL hydrogel. Tissue was harvested24 hours post-treatment, homogenized, and quantitated by serial dilutionand plating.

Compound 100 nearly sterilized the infected tongue following a singletopical dose and was 50-fold more efficacious than Nystatin. Results areshown in FIG. 5A. (Treatment 1=Control; Treatment 2=Compound 100 at 10mg/mL; and Treatment 3=Nyststin at 10 mg/mL). FIG. 5B is aphotomicrograph of a 10 μm section of a tongue from an infected mouse onday 4, stained with PAS (Magnification=100×). Arrows show hyphae andhyphal insertion into tissue.

Example 8 Anti-Candida Activity; In Vitro Profiles

Candida MIC assays were determined in accordance with CLSI guidelinesM27-A3using a clinically isolated C. albicans strain, GDH2346. 50% humanserum was added to determine activity in the presence of serum.

For determination of anti-Candida IC₅₀s, the method was modified byusing RPMI/MOPS buffer pH 6.3 and by addition of FDGlu, a substrate forthe yeast enzyme exoglucanase which is secreted during cell growth. Thisprovides a fluorescent readout for cell growth which was used inaddition to the traditional optical density measure of growth. OD₆₀₀ andfluorescence were determined at 24 and 48 hours and the average of all 4reads was used for the final IC₅₀ determination.

To form the biofilm, yeast were grown in RPMI/MOPS, 0.4% sucrose pH7.4media supplemented with 10% FBS in tissue culture-treated flat bottom 96well plates for 48 hours. The filamentous yeast cultures were thenvigorously washed to remove any non-filamentous, non-attached yeast. Theremaining attached filamentous biofilm yeast were incubated in salinecontaining serially diluted compounds for 24 hours. The cultures wereaspirated to remove compound, rinsed and overlayed with RPMI/MOPS, 0.4%sucrose pH7.4 media, Biofilm viability was measured using a cellproliferation assay (CellTiter96 Aqueous Kit from Promega) and IC50swere determined using Prism GraphPad software (nonlinear fit, Table 3).

Time kills were performed in the same manner as IC₅₀s. At each timepoint yeast were removed, diluted as necessary and plated on YPD agar todetermine viable CFUs.

Bacteria MICs were determined using a broth microdilution assay understandard CLSI conditions Bacteria strains: clinical isolates; yeaststrains: C. dubliniensis (NCPF3949), C. glabrata (ATCC 90030), C. krusei(ATCC 6258), C. parapsilosis (ATCC 22019), and C. tropicalis (ATCC 750).Cytotoxicity (EC₅₀) was determined against mouse 3T3 fibroblasts, humantransformed liver HepG2 cells, and human oral keratinocyte cell line,OKF6/TERT using an MTS viability assay.

Table 3 shows potent activity of several compounds against vegetativeand 2-day hyphal biofilm cultures.

TABLE 3 Anti-C. albicans GDH2346 (μg/ml) Compound Vegetative Hyphal 1644.88 11.04 100 4.93 4.90 136 4.24 0.71 135 1.44 2.68 185 1.09 1.00 1861.03 1.40 187 2.20 ND 188 2.08 2.22

FIGS. 6A and 6B show cidal activity with rapid killing kinetics ofCompound 100 and Compound 135, respectively.

Table 4 shows a subset of compounds active in serum.

TABLE 4 MIC (μg/ml) Cmpd 136 + Cmpd 135 + Compound Cmpd 136 50% HS Cmpd135 50% HS C. albicans 4 2 4 2 GDH2346 C. dubliniensis 8 2 4 1 C.glabrata 4 1 2 2 HS = human serum

Example 9 Activity Against Commensal Bacteria in Oral Acvity and Yeast

Table 5 shows the activity of several compounds against commensalbacteria and different yeast.

TABLE 5 Commensal Bacteria Other Yeast Species MIC (μg/ml) MIC (μg/ml)S. A. C. C. C. C. C. C. Cmpd salivarius viscosis tropicalis parapsilosisdubliniensis glabrata krusei albicans 100 >64 >64 4 8 8 16 8 4-8 136 164 4-8 4-8 8 4 32 4 135 >64 >64 2-4 2 4 2 16 4 137 >64 >64 4 4-8 8-16 8 88 185 8 4 0.5 2 2 2 2 2 186 8 4 0.5 2 2 2 2 2 187 32 8 0.5 4 4 4 4 2 18864 16 0.5 4 4 4 4 2

Example 10 Anti-Fungal Activity; Efficacy in Mouse Candida Sepsis Model

Mice were made neotropenic with i.p. injections of cyclophosphamide (150mg/kg in 10 mL/kg) at 4 and 1 day before inoculation. Each animal wasthen inoculated by injecting 0.1 mL of inoculum of C. albicans in a tailvein. The standard was administered orally and the test compounds by IV1 hour after infection.

The kidneys were collected from four mice in Group 1 at 1 hour afterinfection and from the remaining mice in the study at 24 hours afterinfection. Kidneys were combined in a sterile tube. An aliquot ofsterile PBS were added to each tube and the contents homogenized with atissue homogenizer. Serial dilutions of the tissue homogenates wereconducted, 0.1 mL aliquots were spread on SDA plates and the platesincubated at 35° C. overnight. The CFU/kidneys were determined fromcolony counts. One-way ANOVA with Bonferroni Multiple Comparisons Testwas performed using GraphPad Instat version 3.00 for Windows 95,GraphPad Software, San Diego Calif. USA.

FIG. 7 shows Compound 135 has cidal activity with ≧1.5 log₁₀ reductionsin tissue burden from treatment onset. In contrast, FIG. 8 shows thatcurrent triazole and anti-fungals have a static effect in the model.

Example 11 Disseminated Candidiasis Model; Survival Sturdy

Mice were made neutropenic with i.p. injections of cyclophosphamide (150mg/kg in 10 mL/kg) at 4 and 1 day before inoculation. Each animal wasthen inoculated by injecting 0.1 mL of inoculum of C. albicans in a tailvein. At 2 hours post-infection, the standard was administered orallyand the test compound by IV. Compounds were dosed once daily for 4 days.

The kidneys were collected from four mice in Group 1 at 2 hours afterinfection, from four mice in Groups 2-5 at five days after infection,and from all surviving mice in the infected treatment groups. An aliquotof sterile PBS were added to each tube and the contents homogenized witha tissue homogenizer. Serial dilutions of the tissue homogenates wereconducted, 0.1 mL aliquots were spread on SDA plates and the platesincubated at 35° C. overnight. The CFU/kidneys were determined fromcolony counts.

Survival data was analyzed using the log-rank (Mantel-Cox) test andone-way ANOVA with Tukey's Multiple Comparisons Test was performed onthe yeast density and change in body weight data (GraphPad InStatversion 5.04).

FIG. 9 shows survival of mice over a 14-day period. p<0.01 betweenFluconazole and Compound 135 (10 mg/kg) and p<0.01 between Fluconazoleand Compound 135 (15 mg/kg).

Example 12 Anti-Aspergillus Activity

The in vitro efficacy of a library of compounds was assessed forantifungal activity against A. niger (AN1), A. fumigatus (A1163) and A.flavus (NRRL3357) and compared to that of Itraconazole. For a subset ofcompounds selected based upon efficacy in the screening study a full MICprofile was conducted.

Efficacy of test articles was determined in RPMI 1640 broth with MOPSbuffered to pH7.2 in accordance with CLSI guidelines M38-A forAntifungal Susceptibility Testing of Filamentous Fungi. The method wasmodified by using flat well plates to allow microscopic identificationof growth. The final screening concentration of each test article was 10μM. Assay plates were incubated aerobically at 37° C. for 24-48 hours.Following incubation, plates were assessed visually (by eye andmicroscopically) for inhibition of growth. Inhibition was recorded at50%, 80% and 100% inhibition compared to the positive control. A hit wasdescribed as a well demonstrating 100% inhibition.

MICs were determined in RPMI 1640 broth plus MOPS buffered to pH7.2 inaccordance with CLSI guidelines M38-A for Antifungal SusceptibilityTesting of Filamentous Fungi. The method was modified by using flat wellplates to allow microscopic identification of growth. The final MICrange was 64-0.125 μg/mL.

Table 6 shows several compounds have broad anti-fungal activity with lowmammalian cell cytotoxicity.

TABLE 6 IC₅₀ Cytotoxicity % Inhibition (μg/ml) EC₅₀ (μM) A. A. A. C.Mouse Human Compound fumigatus niger flavus albicans 3T3 HepG2 Cmpd 184100 100 100 3.1 1000 155 Cmpd 183 100 100 100 2.0 478 1000 Cmpd 136 100100 100 1.4 311 453 Cmpd 165 80 100 100 1.1 115 138

Various modifications of the disclosure, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference (including, but not limitedto, journal articles, U.S. and non-U.S. patents, patent applicationpublications, international patent application publications, gene bankaccession numbers, and the like) cited in the present application isincorporated herein by reference in its entirety.

1-76. (canceled)
 77. A method of preventing or treating a human havingoral or disseminated candidiasis or an aspergillus infection comprisingadministering to the human in need thereof an effective amount of acompound of Formula IV:

wherein: R¹ and R² are, independently, —C(═NH)NH₂, —(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═NH)NH₂, where n is 2, 3, or 4; or a pharmaceuticallyacceptable salt thereof. 78-252. (canceled)
 253. The method of claim 77wherein R¹ and R² are, independently, —C(═NH)NH₂, —(CH₂)_(n)NH₂, or—(CH₂)_(n)NC(═NH)NH₂, where n is 2 or
 3. 254. The method of claim 77wherein R¹ and R² are, independently, —C(═NH)NH₂ or —(CH₂)_(n)NH₂, wheren is 2 or
 3. 255. The method of claim 77 wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 256. The method of claim77 wherein the compound, or pharmaceutically acceptable salt thereof,that is administered to the human is in a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier.
 257. The method ofclaim 256 wherein the pharmaceutical composition is in a unit dosageform.
 258. The method of claim 257 wherein the unit dosage form is apackaged preparation.
 259. The method of claim 257 wherein the unitdosage form is a tablet or capsule.
 260. The method of claim 77 whereinthe human has oral or disseminated candidiasis infection.
 261. Themethod of claim 77 wherein the human has an aspergillus infection.